WO2016124140A1 - 杂环取代的n-磺酰基苯甲酰胺衍生物、其制法与医药上的用途 - Google Patents

杂环取代的n-磺酰基苯甲酰胺衍生物、其制法与医药上的用途 Download PDF

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WO2016124140A1
WO2016124140A1 PCT/CN2016/073387 CN2016073387W WO2016124140A1 WO 2016124140 A1 WO2016124140 A1 WO 2016124140A1 CN 2016073387 W CN2016073387 W CN 2016073387W WO 2016124140 A1 WO2016124140 A1 WO 2016124140A1
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ring
halogenated
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兰炯
周福生
赵金柱
黄栋
谢婧
胡毅
吕强
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上海海雁医药科技有限公司
扬子江药业集团有限公司
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Priority to CN201680007143.2A priority Critical patent/CN107207430B/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/402—1-aryl substituted, e.g. piretanide
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

Definitions

  • the invention belongs to the field of medical technology.
  • the present invention relates in particular to a heterocyclic substituted N-sulfonylbenzamide derivative, a process for its preparation and its use as a sodium ion channel (particularly Nav1.7) inhibitor, and a pharmaceutical combination prepared therefrom And pharmaceutical compositions.
  • Nav1.7 (PN1, SCN9A) VGSC is sensitive to the blocking of tetrodotoxin, which is mainly expressed in peripheral sympathetic neurons and sensory neurons.
  • the SCN9A gene has been replicated by a variety of species including humans, rats and rabbits and shows approximately 90% identity of amino acids between human and rat genes.
  • Nav1.7 plays an important role in a variety of pain states, including acute, chronic, inflammatory, and/or neuropathic pain.
  • Nav1.7 protein accumulates in neuromas, Especially the neuroma that causes pain.
  • Mutations in Nav1.7 function have been implicated in primary erythematous limb pain (a disease characterized by burning and inflammation of the extremities), and sudden extreme pain.
  • Reports on the use of non-selective sodium channel blockers lidocaine and mexiletine to alleviate the symptoms of hereditary erythematous limb pain, and the extent and severity of carbamazepine that effectively reduce the invasion of PEPD are consistent with the above observations. .
  • Nav1.7 is specifically expressed in DRG sensory neurons and not in other tissues such as cardiomyocytes and central nervous system, the development of its specific blockers for the treatment of chronic pain may not only improve the efficacy, but also greatly reduce the side effects. And selective inhibitors of the Nav1.7 ion channel are used in almost all types of pain treatment.
  • the Nav1.7 ion channel is an important target for the development of non-addictive analgesic drugs.
  • the highly selective inhibitor of Nav1.7 ion channel can be used for a wide range of pain treatments. Therefore, the development of a novel Nav1.7 ion channel highly selective inhibitor is very necessary.
  • a first aspect of the invention provides a compound of formula (II), or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof:
  • R 1 , R 2 , R 3 and R 4 are each independently hydrogen, hydroxy, CN, NO 2 , halogen, -NR a R b , C 1-20 alkyl, C 3-20 cycloalkyl, C 3-20 cycloalkoxy, C 2-20 alkenyl, C 2-20 alkynyl, C 1-20 alkoxy, -CHO, -CO-(C 1-20 alkyl), -CO-( C 6-20 aryl), C 6-20 aryl, -CONR a R b , -C(O)O-(C 1-20 alkyl), -OC(O)-(C 1-20 alkyl ), -SO 2 -(C 1-20 alkyl) or -SO 2 -(C 6-20 aryl);
  • R 5 is hydrogen, C 1-20 alkyl, C 3-20 cycloalkyl, halogenated C 1-20 alkyl;
  • R 6 is C 6-20 aryl, C 1-20 alkyl, -NR a R b ; wherein R a and R b are each independently hydrogen, C 1-20 alkyl, C 3-20 cycloalkyl Or a C 6-20 aryl group;
  • L 1 is attached at any different position on the ring and is a bond, or -C(O)N(R y )-, -N(R y )C(O)-, -N(R y )SO 2 - , -SO 2 N(R y )-, -OC(O)-, -C(O)O-, -(CR y R x ) r1 (O) r2 (CR y R x ) r3 -, -S( O)-, -SO 2 -, -N(R y )-, -O-, -S-, -C(O)- or cyclopropylene; wherein R y and R x are each independently hydrogen, Halogen, hydroxy, CN, NO 2 , C 1-20 alkyl, halogenated C 1-20 alkyl, C 3-20 cycloalkyl, C 2-20 alkenyl, C 2-20 alkynyl or C 6-
  • W 1 and W 2 are each independently C, N, O or S;
  • n, m are each independently 0, 1, 2 or 3, and n, m are not 0 at the same time; wherein, when n is 0 or m is 0, W 1 and W 2 are connected by a single bond;
  • R 0 ) p is a hydrogen at any position on the ring substituted by p R 0 , p is 0, 1, 2, 3, 4 or 5, and each R 0 is the same or different, and each independently is hydrogen, helium, C 1-20 alkyl, deuterated C 1-20 alkyl or halogenated C 1-20 alkyl; or any two R 0 are linked by a single bond or -(CH 2 ) p1 -, p1 is 1, 2 or 3;
  • A is a C 6-20 aryl group, a 3 to 7 membered monocyclic ring, an 8 to 10 membered bicyclic ring, a 3 to 7 membered monoheterocyclic ring, an 8 to 10 membered bicyclic heterocyclic ring, a 5 or 6 membered monocyclic heteroaryl ring, and 8 Up to 10 membered bicyclic heteroaryl ring, benzo 3 to 7 membered monocyclic ring, benzo 3 to 7 membered monoheterocyclic ring, 5 to 6 membered monocyclic heteroaryl ring and 3 to 7 membered monocyclic ring, 5 to 6 membered a monocyclic heteroaryl ring and a 3 to 7 membered monoheterocyclic ring;
  • A, L 1 and R 0 are as defined above.
  • W 1 is N, O, S or C
  • W 1 is O or S
  • L 1 is bonded to any carbon atom other than W 1 and W 2 on the ring
  • W 1 is In the case of N or C
  • L 1 is bonded to any ring atom other than W 2 on the ring
  • L 1 is bonded to W 1 .
  • each R 0 is the same or different and is each independently hydrogen.
  • A is a C 6-20 aryl group or a 5 or 6 membered monocyclic heteroaryl ring.
  • A is a phenyl or pyridyl group; said phenyl or pyridyl group is substituted or unsubstituted; and said substitution means that 1 to 5 hydrogens in the group are selected from Substituted by the following group of substituents: halogen, C 1-20 alkyl, halogenated C 1-20 alkyl, C 1-20 alkoxy, halogenated C 1-20 alkoxy, C 3-20 naphthenic a group, and a C 3-20 cycloalkoxy group.
  • L 1 is a bond, or -(CR y R x ) r1 (O) r2 (CR y R x ) r3 -; wherein R y , R x are each independently hydrogen; r1 R3 is each independently 0, 1, 2 or 3; r2 is 0 or 1.
  • L 1 is -(CR y R x ) r1 (O) r2 (CR y R x ) r3 -; wherein R y , R x are each independently hydrogen; r 1 is 1 or 2; R2 is 1; r3 is 0 or 1.
  • the compound is a compound of formula (III):
  • R 0 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R x , R y , r1, r2, r3, A, W 1 , W 2 , n, p, m are as defined above Defined.
  • W 1 is N, O, S or C, and when W 1 is O or S, (CR y R x ) r1 and W 1 and W 2 are removed from the ring. Any other carbon atom other than the connection, when W 1 is N or C, (CR y R x ) r1 is bonded to any ring atom other than W 2 on the ring, and r1 is as defined above.
  • W 2 is N.
  • W 1 is N, O, S or C.
  • A is wherein R 1 ', R 2 ', R 3 ', R 4 ', R 5 ' are as defined in the specification.
  • A is or Wherein R 21 , R 31 , R 41 , R 51 , R 12 , R 32 , R 42 , R 52 , R 13 , R 23 , R 43 , R 53 are each independently hydrogen, halogen, nitro, hydroxy, cyanide , C 6-20 aryl, C 1-20 alkyl, halo C 1-20 alkyl, halo C 1-20 alkoxy, C 1-20 alkoxy, C 3-20 cycloalkyl Halogenated C 3-20 cycloalkyl, C 3-20 cycloalkoxy, halo C 3-20 cycloalkoxy, C 2-20 alkenyl, halogenated C 2-20 alkenyl, C 2 - 20 alkynyl, halogenated C 2-20 alkynyl, -NR a R b , -C(O)NR a R b , -N(R a )C(O)-(C 1-20 alkyl), - N
  • the compound is a compound of formula (IV):
  • R 0 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R x , R y , r1, r2, r3, A, W 2 , n, p, m are as defined above; W 1 is N or C.
  • r2 is zero.
  • r1 and r3 are 0; r2 is 1.
  • r1 is 1, 2 or 3; r2 is 1; r3 is 0.
  • r1, r2, and r3 are zero.
  • the compound is a compound of formula (V):
  • R 0 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 1 , W 1 , W 2 , n, p, m are as defined above;
  • R 1 ', R 2 ', R 3 ', R 4 ', R 5 ' are each independently hydrogen, halogen, nitro, hydroxy, cyano, C 6-20 aryl, C 1-20 alkyl, halo C 1-20 alkyl, Halogenated C 1-20 alkoxy, C 1-20 alkoxy, C 3-20 cycloalkyl, halogenated C 3-20 cycloalkyl, C 3-20 cycloalkoxy, halogenated C 3- 20 cycloalkoxy, C 2-20 alkenyl, halogenated C 2-20 alkenyl, C 2-20 alkynyl, halogenated C 2-20 alkynyl, -NR a R b , -C(O)NR a R b ,
  • R 1 ', R 2 ', R 3 ', R 4 ', R 5 ' are each independently hydrogen, halogen, C 1-20 alkyl, halo C 1-20 alkyl, Halogenated C 1-20 alkoxy, C 1-20 alkoxy, C 3-20 cycloalkyl, C 3-20 cycloalkoxy.
  • R 21 , R 31 , R 41 , R 51 , R 12 , R 32 , R 42 , R 52 , R 13 , R 23 , R 43 , R 53 are each independently hydrogen, halogen, C 1-20 alkyl, halo C 1-20 alkyl, halo C 1-20 alkoxy, C 1-20 alkoxy, C 3-20 cycloalkyl, C 3-20 cycloalkoxy .
  • L 1 is -(CR y R x ) r1 (O) r2 (CR y R x ) r3 -, and r1, r2, and r3 are as defined above.
  • W 1 is N, O, S or C, and when W 1 is O or S, L 1 and any carbon other than W 1 and W 2 on the ring The atom is bonded.
  • W 1 is N or C, L 1 is bonded to any ring atom other than W 2 on the ring.
  • L 1 is bonded to W 1 .
  • W 2 is N.
  • R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, halogen, C 1-20 alkyl, C 3-20 cycloalkyl;
  • R 5 is hydrogen
  • R 6 is C 1-20 alkyl, -NR a R b ;
  • R a and R b are each independently hydrogen or a C 1-20 alkyl group
  • W 1 , W 2 are each independently C, O, S or N;
  • L 1 is a bond, or -(CR y R x ) r1 (O) r2 (CR y R x ) r3 -, -O- or -C(O)-; wherein R y and R x are each independently Hydrogen; r1, r3 are each independently 0 or 1; r2 is 0 or 1;
  • n, m are each independently 1 or 2;
  • (R 0 ) p is a hydrogen at any position on the ring is replaced by p R 0 , p is 0;
  • A is a phenyl group
  • W 1 and/or W 2 is N or C
  • A is bonded to any ring atom other than W 1 on the ring
  • L 1 is bonded to any ring atom other than W 2 on the ring
  • alkyl group, cycloalkyl group or phenyl group is substituted or unsubstituted; and the substitution means that 1 to 5 hydrogens in the group are substituted with a substituent selected from the group consisting of halogen, C 1-20 alkyl, halogenated C 1-20 alkyl, C 1-20 alkoxy, halogenated C 1-20 alkoxy.
  • R 2 and R 4 are hydrogen, and R 1 and R 3 are each independently halogen, C 3-6 cycloalkyl, C 1-3 alkyl, C 3-6 cycloalkoxy. Or C 1-3 alkoxy.
  • R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, halogen, C 1-20 alkyl, C 3-20 cycloalkyl;
  • R 5 is hydrogen
  • R 6 is C 1-20 alkyl, -NR a R b ; wherein R a and R b are each independently hydrogen, C 1-20 alkyl;
  • A is a C 6-20 aryl group or a 5 or 6 membered monocyclic heteroaryl ring
  • L 1 is a bond, or -(CR y R x ) r1 (O) r2 (CR y R x ) r3 -; wherein R y and R x are each independently hydrogen; r1 and r3 are each independently 0. 1, 2 or 3; r2 is 0 or 1;
  • Each R 0 is the same or different and is each independently hydrogen
  • the alkyl, cycloalkyl, aryl, 5- or 6-membered monocyclic heteroaryl ring is substituted or unsubstituted; and the substitution means that 1 to 5 hydrogens in the group are selected from Substituted by a group of substituents: halogen, nitro, hydroxy, cyano, C 6-20 aryl, C 1-20 alkyl, halo C 1-20 alkyl, C 1-20 alkoxy, halogenated C 1-20 alkoxy, C 3-20 cycloalkyl, halogenated C 3-20 cycloalkyl, C 3-20 cycloalkoxy, halogenated C 3-20 cycloalkoxy, C 2-20 Alkenyl, halogenated C 2-20 alkenyl, C 2-20 alkynyl, halogenated C 2-20 alkynyl, C 1-20 alkylthio, halogenated C 1-20 alkylthio, C 1-20 An alkylamino group, a hal
  • the phenyl group is wherein R 1 ', R 2 ', R 3 ', R 4 ', R 5 ' are each independently hydrogen, halogen, C 1-20 alkyl, halo C 1-20 alkyl, halo C 1-20 Alkoxy, C 1-20 alkoxy, C 3-20 cycloalkyl, C 3-20 cycloalkoxy.
  • the pyridyl group is or Wherein R 21 , R 31 , R 41 , R 51 , R 12 , R 32 , R 42 , R 52 , R 13 , R 23 , R 43 , R 53 are each independently hydrogen, halogen, C 1-20 alkyl Halogenated C 1-20 alkyl, halo C 1-20 alkoxy, C 1-20 alkoxy, C 3-20 cycloalkyl, C 3-20 cycloalkoxy.
  • L 1 is a bond, or -(CR y R x ) r1 (O) r2 (CR y R x ) r3 -; wherein R y and R x are each independently hydrogen; r1 and r3 are each independently 0. 1, 2 or 3; r2 is 0 or 1;
  • Each R 0 is the same or different and is each independently hydrogen.
  • R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, halogen, C 1-20 alkyl, C 3-20 cycloalkyl;
  • R 5 is hydrogen
  • R 6 is C 1-20 alkyl, -NR a R b ; wherein R a and R b are each independently hydrogen or a C 1-20 alkyl group.
  • r1 is 1, 2 or 3; r2 is 1; r3 is 0.
  • R 1 and R 3 are each independently hydrogen, halogen, C 1-20 alkyl or C 3-20 cycloalkyl; and R 2 and R 4 are hydrogen.
  • the C 1-20 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl.
  • the C 3-20 cycloalkyl group is a cyclopropyl group.
  • the halo C 1-20 alkyl group is a trifluoromethyl group.
  • the halo C 1-20 alkoxy group is a trifluoromethoxy group, a trifluoroethoxy group, or a difluoromethoxy group.
  • the C 1-20 alkoxy group is a methoxy group, an ethoxy group, an isopropoxy group, a t-butoxy group, or an isobutoxy group.
  • the C 3-20 cycloalkoxy group is a cyclopropoxy group.
  • the halogen is fluorine or chlorine.
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • the R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R a , R b , L 1 , R y , R x , W 1 , W 2 , n And m, R 0 , A and the like are each independently the corresponding group of each of the compounds of the specific formula II in the examples.
  • the compound of formula II of the present invention is each specific compound noted in the Examples section, especially any of Z-22 to Z-168.
  • the compound is a compound prepared in the examples of the present application.
  • a second aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the first aspect of the invention, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof; and pharmaceutically acceptable Acceptable carrier.
  • a third aspect of the invention provides a compound according to the first aspect of the invention, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, or a pharmaceutical composition according to the second aspect of the invention Use in the preparation of a medicament for treating a disease or condition.
  • the disease or condition is selected from the group consisting of pain, depression, cardiovascular disease, respiratory disease, mental illness, or a combination thereof.
  • the disease or condition is selected from the group consisting of HIV-related pain, HIV treatment-induced neuropathy, trigeminal neuralgia, post-herpetic neuralgia, acute pain, heat sensitivity, sarcoidosis, intestinal tract Jain syndrome, Crohn's disease, pain associated with multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, bone and joint Inflammation, atherosclerosis, sudden dystonia, myasthenia gravis syndrome, myotonia, malignant hyperthermia, cystic fibrosis, pseudohyperaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety , schizophrenia, sodium channel toxin-related disorders, familial erythematous limb pain, primary erythematous limb pain, familial rectal pain, cancer, epilepsy, local and generalized tonic seizures, restless legs syndrome, Arrhythmia
  • the pain is selected from the group consisting of neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, traumatic pain, surgical pain, post-operative pain, production pain, labor pain, toothache, chronic pain, Persistent pain, peripheral-mediated pain, centrally mediated pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, peripheral nerve injury, trigeminal neuralgia, post-herpetic neuralgia, acute Pain, familial erythematous limb pain, primary erythematous limb pain, familial rectal pain or fibromyalgia or a combination thereof.
  • a fourth aspect of the invention provides a method of treating a disease or condition in a mammal, the method comprising administering to a subject in need thereof, such as a mammal, a therapeutically effective amount of a compound of the first aspect of the invention, or a pharmaceutical thereof An acceptable salt, solvate, stereoisomer or prodrug, or a pharmaceutical composition of the second aspect of the invention.
  • Figure 1 shows the baseline of rat cold pain test in compound Z-40 in a rat model of spinal nerve ligation.
  • Figure 2 shows that Compound Z-40 inhibits cold stimulating hyperalgesia in a rat model of spinal nerve ligation.
  • Figure 3 shows the baseline of rat cold pain test in compound Z-73 in a rat model of spinal nerve ligation.
  • Figure 4 shows that Compound Z-73 inhibits cold stimulating hyperalgesia in a rat model of spinal nerve ligation.
  • Figure 5 shows the baseline of rat cold pain test in compound Z-22 in a rat model of spinal nerve ligation.
  • Figure 6 shows the effect of compound Z-22 on the inhibition of cold-stimulated hyperalgesia in a rat model of spinal nerve ligation.
  • Figure 7 shows the cold pain tester of rats in the rat model of spinal nerve ligation by compounds Z-47 and Z-54. line.
  • Figure 8 shows that compounds Z-47 and Z-54 inhibit cold-stimulated hyperalgesia in a rat model of spinal nerve ligation.
  • the heterocyclic-substituted N-sulfonylbenzamide derivative of the present invention has a high inhibitory activity against Nav1.7, and has an inhibitory activity against Nav1.5. It is weak and has obvious selective inhibitory activity against Nav1.7.
  • a significant analgesic effect is also shown in the pain model test, and thus the series of compounds of the present invention can be developed into drugs for the treatment of a wide range of pain.
  • C 1-20 alkyl refers to a straight-chain or branched saturated aliphatic hydrocarbon group containing from 1 to 20 carbon atoms, as defined below; more preferably C 1-10 alkyl, non-limiting Examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1, 2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methyl Propyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3- Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylp
  • alkenyl refers to an aliphatic hydrocarbon group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond
  • C 2-20 alkenyl means having from 2 to 20 carbon atoms.
  • the linear and branched alkenyl groups are similarly defined as follows; more preferably C 2-10 alkenyl; more preferably C 2-6 alkenyl; most preferably C 2-4 alkenyl, such as vinyl, 1-propenyl , 2-propenyl, 1-, 2- or 3-butenyl, and the like.
  • alkynyl refers to an aliphatic hydrocarbon radical as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond
  • C 2-20 alkynyl is meant to contain from 2 to 20 carbon atoms.
  • the straight-chain and branched alkynyl groups are similarly defined as follows; more preferably C 2-10 alkynyl; more preferably C 2-6 alkynyl; more preferably C 2-4 alkynyl; for example ethynyl, 1-propenyl Alkynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group
  • C 3-20 cycloalkyl refers to a cyclic hydrocarbon group containing from 3 to 20 carbon atoms, as defined below; More preferably, it is a C 3-10 cycloalkyl group; more preferably a C 3-8 cycloalkyl group; most preferably a C 3-6 cycloalkyl group.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptene
  • the alkenyl group, the cyclooctyl group and the like are preferably a cyclopropyl group, a cyclopentyl group or a cyclohexenyl group.
  • Non-limiting examples of polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.
  • heterocycloalkyl and “heterocyclyl” are used interchangeably and mean a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, preferably a 3 to 20 membered heterocycloalkyl group.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, tetrahydrofuranyl and the like.
  • Non-limiting examples of polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • partially unsaturated refers to a pi-electron system that contains one or more unsaturated bonds but does not have a complete conjugation.
  • C 1-20 alkoxy refers to -O-(C 1-20 alkyl), wherein alkyl is as defined above.
  • a C 1-10 alkoxy group is preferred, a C 1-6 alkoxy group is more preferred, and a C 1-3 alkoxy group is most preferred.
  • Non-limiting examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, pentyloxy and the like.
  • C 3-20 cycloalkoxy refers to -O-(C 3-20 cycloalkyl), wherein cycloalkyl is as defined above.
  • a C 3-10 cycloalkoxy group is preferred, preferably a C 3-8 cycloalkoxy group, more preferably a C 3-6 cycloalkoxy group.
  • Non-limiting examples include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • C 6-20 aryl refers to an all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, meaning 6 to 20 An aryl group of a carbon atom; more preferably a C 6-12 aryl group, more preferably a phenyl group and a naphthyl group, and most preferably a phenyl group.
  • a bond refers to the attachment of two groups attached thereto through a covalent bond.
  • halogen refers to fluoro, chloro, bromo or iodo.
  • halo means that one or more (eg 1, 2, 3, 4 or 5) hydrogens in the group are replaced by a halogen.
  • halo C 1-20 alkyl refers to an alkyl group substituted with one or more (eg 1, 2, 3, 4 or 5) halogens, wherein alkyl is as defined above. It is preferably a halogenated C 1-10 alkyl group, more preferably a halogenated C 1-6 alkyl group, and most preferably a halogenated C 1-3 alkyl group.
  • halogenated C 1-20 alkyl groups include, but are not limited to, monochloroethyl, dichloromethyl, 1,2-dichloroethyl, monobromoethyl, monofluoroethyl, monofluoromethyl, Difluoromethyl, trifluoromethyl, and the like.
  • halo C 1-20 alkoxy means that the alkoxy group is substituted by one or more (eg 1, 2, 3, 4 or 5) halogens, wherein the alkoxy group is as defined above. It is preferably a halogenated C 1-10 alkoxy group, more preferably a halogenated C 1-6 alkoxy group, and most preferably a halogenated C 1-3 alkoxy group. These include, but are not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, and the like.
  • halo C 3-20 cycloalkyl refers to a cycloalkyl group substituted with one or more (eg, 1, 2, 3, 4, or 5) halo, wherein cycloalkyl is as defined above.
  • Preferred is a halogenated C 3-10 cycloalkyl group, more preferably a halogenated C 3-8 cycloalkyl group, and most preferably a halogenated C 3-6 cycloalkyl group.
  • halogenated C 3-10 cycloalkyl group more preferably a halogenated C 3-8 cycloalkyl group, and most preferably a halogenated C 3-6 cycloalkyl group.
  • These include, but are not limited to, trifluorocyclopropyl, monofluorocyclopropyl, monofluorocyclohexyl, difluorocyclopropyl, difluorocyclohexyl, and the like.
  • deuterated C 1-20 alkyl refers to an alkyl group substituted with one or more (eg 1, 2, 3, 4 or 5) deuterium atoms, wherein alkyl is as defined above. It is preferably a deuterated C 1-10 alkyl group, more preferably a deuterated C 1-6 alkyl group, and most preferably a deuterated C 1-3 alkyl group. Examples of deuterated C 1-20 alkyl groups include, but are not limited to, monodeuterated methyl, monodeuterated ethyl, dideuterated methyl, didecanoethyl, triterpene methyl, triterpenoid Base.
  • C 1-20 hydroxyalkyl refers to a C 1-20 alkyl group substituted with a hydroxy group, wherein alkyl is as defined above. It is preferably a C 1-10 hydroxyalkyl group, more preferably a C 1-6 hydroxyalkyl group, and most preferably a C 1-3 hydroxyalkyl group.
  • amino means -NH 2
  • cyano refers to -CN
  • Niro refers to -NO 2
  • benzyl refers to -CH 2 - phenyl
  • Carboxy means -C(O)OH
  • thiol means -SH
  • cyclopropylene structure is:
  • Carboxylate group refers to -C(O)O-( C1-20 alkyl) or ( C3-20 cycloalkyl), wherein alkyl, cycloalkyl are as defined above.
  • C 1-20 alkylthio refers to -S-(C 1-20 alkyl), wherein alkyl is as defined above. It is preferably a C 1-10 alkylthio group, more preferably a C 1-6 alkylthio group, and most preferably a C 1-3 alkylthio group.
  • C 1-20 alkylamino refers to -(C 1-20 alkyl)-NH 2 or -NH 2 -(C 1-20 alkyl), wherein alkyl is as defined above. It is preferably a C 1-10 alkylamino group, more preferably a C 1-6 alkylamino group, and most preferably a C 1-3 alkylamino group.
  • C 3-20 cycloalkylthio refers to -S-(C 3-20 cycloalkyl), wherein cycloalkyl is as defined above. It is preferably a C 3-10 cycloalkylthio group, more preferably a C 3-8 cycloalkylthio group, and most preferably a C 3-6 cycloalkylthio group.
  • 3-membered to 20-membered heterocycloalkylthio refers to -S-(3- to 20-membered heterocycloalkyl), wherein heterocycloalkyl is as defined above. It is preferably a 3- to 10-membered heterocycloalkylthio group.
  • 3-membered to 20-membered heterocycloalkyloxy refers to -O- (3- to 20-membered heterocycloalkyl), wherein heterocycloalkyl is as defined above. It is preferably a 3- to 10-membered heterocycloalkyloxy group.
  • heteroaryl ring and “heteroaryl” are used interchangeably and mean having 5 to 10 ring atoms, preferably 5 or 6 membered monocyclic heteroaryl or 8 to 10 membered bicyclic heteroaryl.
  • the ring array shares 6, 10 or 14 ⁇ electrons; and has a group of 1 to 5 hetero atoms in addition to carbon atoms.
  • Hetero atom means nitrogen, oxygen or sulfur.
  • 3- to 7-membered monocyclic refers to a saturated or partially unsaturated, all-carbon monocyclic ring containing from 3 to 7 ring atoms. It is preferably 5 to 6 yuan.
  • monocyclic rings include, but are not limited to, cyclopropyl rings, cyclobutyl rings, cyclopentyl rings, cyclopentenyl rings, cyclohexyl rings, cyclohexenyl rings, cyclohexadienyl rings, cycloheptyl groups. Ring, cycloheptatrienyl ring, cyclooctyl ring, and the like.
  • 3 to 7 membered monoheterocycle means that 1, 2 or 3 carbon atoms in a 3 to 7 membered monocyclic ring are substituted with a heteroatom selected from nitrogen, oxygen or sulfur. It is preferably 5 to 6 yuan.
  • monoheterocycles include, but are not limited to, tetrahydrofuran ring, tetrahydrothiophene ring, pyrrolidinyl ring, piperidine ring, pyrroline ring, oxazolidine ring, piperazine ring, dioxolane, morpholine ring, Thiomorpholine ring, homopiperazine ring, pyran ring and the like.
  • 8- to 10-membered bicyclic refers to a saturated all-carbon bicyclic or partially unsaturated, all-carbon bicyclic ring containing from 8 to 10 ring atoms, examples of which include, but are not limited to:
  • 8- to 10-membered bicyclic heterocycle means that 1, 2, 3, 4 or 5 carbon atoms in the 8- to 10-membered bicyclic ring are replaced by a heteroatom selected from nitrogen, oxygen or sulfur.
  • bicyclic heterocycles include, but are not limited to, tetrahydroquinoline rings, tetrahydroisoquinoline rings, decahydroquinoline rings, and the like.
  • a "5- to 6-membered monocyclic heteroaryl ring” refers to a monoheteroaryl ring containing from 5 to 6 ring atoms, including, for example, but not limited to, a thiophene ring, an N-alkylpyrrole ring, Furan ring, thiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring, Pyrimidine ring, pyrazine ring and the like.
  • 8- to 10-membered bicyclic heteroaryl ring refers to a biheteroaryl ring containing from 8 to 10 ring atoms, and includes, for example, but not limited to: benzofuran ring, benzothiophene ring, hydrazine Anthracene ring, isoindole ring, quinoline ring, isoquinoline ring, indazole ring, benzothiazole ring, benzimidazole ring, quinazoline ring, quinoxaline ring, porphyrin ring, pyridazine ring.
  • benzo 3 to 7 membered monocyclic or benzo 3 to 7 membered monoheterocyclic ring means a bicyclic structure formed by condensing a monocyclic or monoheterocyclic ring having 3 to 7 ring atoms to a benzene ring.
  • the benzo is a 5- to 6-membered monocyclic or benzo 5- to 6-membered monoheterocyclic ring.
  • Non-limiting examples include:
  • 5 to 6 membered monocyclic heteroaryl ring and 3 to 7 membered monocyclic or 5 to 6 membered monocyclic heteroaryl ring and 3 to 7 membered monoheterocyclic ring means a 3 to 7 membered single ring. Or a 3 to 7 membered monoheterocyclic ring fused to a bicyclic structure formed on a 5 to 6 membered monocyclic heteroaryl ring, non-limiting examples comprising:
  • substituted refers to one or more hydrogen atoms in the group, preferably 1 to 5 hydrogen atoms are independently substituted with each other by a corresponding number of substituents, more preferably 1 to 3 hydrogen atoms are independent of each other. The ground is replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • alkyl may be substituted or unsubstituted
  • alkenyl may be substituted or unsubstituted
  • alkynyl may be substituted or unsubstituted
  • cycloalkyl may be substituted or unsubstituted
  • hetero The cyclo group may be substituted or unsubstituted
  • the alkoxy group may be optionally substituted or unsubstituted
  • the cycloalkoxy group may be optionally substituted or unsubstituted
  • the aryl group may be substituted or unsubstituted.
  • the 3 to 7 membered monocyclic ring may be substituted or unsubstituted
  • the 3 to 7 membered monocyclic heterocyclic ring may be substituted or unsubstituted
  • the 8 to 10 membered bicyclic ring may be substituted or unsubstituted, 8 to 10 membered.
  • the bicyclic heterocycle may be substituted or unsubstituted, and the benzo 3 to 7 membered monocyclic or benzo 3 to 7 membered monoheterocyclic ring may be substituted or unsubstituted, 5 to 6 membered monocyclic heteroaryl ring and
  • the 3- to 7-membered monocyclic or 5- to 6-membered monocyclic heteroaryl ring and the 3- to 7-membered monoheterocyclic ring may be substituted or unsubstituted, and when the above group is substituted, the substituent is preferably 1 to 5 or less.
  • the present invention provides a process for the preparation of a compound of formula (II), which compounds can be readily prepared by a variety of synthetic procedures which are well known to those skilled in the art. Exemplary methods of preparation of these compounds can include, but are not limited to, the procedures described below.
  • the compound of the formula (II) of the present invention can be produced by referring to the following synthetic route, and the steps in the method can be expanded or combined as needed during the specific operation.
  • Step 1 The carboxyl group in the compound of formula (Ia) can be activated first by a reagent such as oxalyl chloride, carbonyldiimidazole (CDI), propylphosphonic anhydride, urea-based amide coupling agent or carbodiimide, followed by affinity Alkaloids such as 4-dimethylaminopyridine, N,N-dimethylaminopropyl-N'-ethylcarbodiimide, 4-dimethylaminopyridine/N,N- Displacement reaction with a sulfonamide group in the compound of formula (I-b) in the presence of diisopropylethylamine to form a compound of formula (I-c).
  • a reagent such as oxalyl chloride, carbonyldiimidazole (CDI), propylphosphonic anhydride, urea-based amide coupling agent or carbodiimide
  • affinity Alkaloids such as 4-dimethyl
  • Step 2 a compound of the formula (Ic) and a compound of the formula (Id) are produced in the presence of a base system by a substitution reaction (for example, an affinity substitution reaction or the like) or a coupling reaction (such as a Suzuki coupling or the like) to form a compound of the formula (Ie).
  • a substitution reaction for example, an affinity substitution reaction or the like
  • a coupling reaction such as a Suzuki coupling or the like
  • Suitable base systems include potassium t-butoxide present in DMSO, sodium hydride present in DMF, potassium carbonate present in DMF, and the like.
  • Step 3 A compound of the formula (Ie) can be substituted with a compound of the formula (If) to form a compound of the formula (II), and Lev in the formula (If) is a leaving group including, but not limited to, a triflate Chlorine, bromine, iodine; sulfonate group, such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonate, etc.; acyloxy, such as acetoxy, trifluoroacetoxy Base.
  • the compound of formula (Id) may be first substituted with a compound of formula (If) to form a compound of formula (Ig), followed by reaction with a compound of formula (Ic) to form a compound of formula (II), the reaction conditions being the same as step 3 and step in Scheme 1, respectively. 2.
  • a series of novel heterocyclic substituted N-sulfonylbenzamide derivatives are provided which have high selective inhibitory activity against Nav1.7 and are useful as drugs for the treatment of a wide range of pains.
  • DMF is dimethylformamide
  • DMSO is dimethyl sulfoxide
  • THF is tetrahydrofuran
  • DIEA is N,N-diisopropylethylamine
  • EA is ethyl acetate
  • PE is petroleum ether
  • BINAP is (2R,3S)-2,2'-bisdiphenylphosphino-1,1'-binaphthyl.
  • room temperature means about 25 °C.
  • Step a Compound 1-a-1 (14.8 g, 0.10 mol) was added to trifluoromethanesulfonic acid (150 ml), the mixture was cooled to 0 ° C, and N-iodosuccinimide (24.75 g) was added portionwise. , 0.110 mol). The mixture was stirred at room temperature for 2 h. The reaction solution was slowly poured into ice water and stirred for about 15 minutes. Extract with petroleum ether (3 x 100 ml). The organic phase was washed with aqueous sodium thiosulfite (100 mL). The filtrate was evaporated to dryness.
  • Step b Compound 1-a-2 (14 g, 0.051 mol) was dissolved in 1,4-dioxane (140 ml) under N 2 and added triethylamine (15.6 g, 0.153 mol). Water (10 ml), 1,1 '-bis(diphenylphosphino)ferrocene palladium (II) dichloromethane complex (2.08 g, 2.55 mmol). The mixture was stirred at 80 ° C for 18 h under a pressure of 10 kg of carbon monoxide. The reaction mixture was slowly warmed to room temperature, then aqueous 1N EtOAc (250 mL). The aqueous phase was adjusted to pH 2 with 1N aqueous HCl.
  • Step c Compound 1-a-3 (7.8 g, 0.041 mol) was dissolved in anhydrous dichloromethane (100 mL) under N 2 and then added 1-ethyl-(3-dimethylaminopropyl) Carbodiimide hydrochloride (11.65 g, 0.061 mol), DMAP (11.07 g, 0.090 mol). The mixture was stirred at room temperature for 10 minutes and methanesulfonamide 2 (4.82 g, 0.061 mol). The mixture was stirred at room temperature for 18 h. 150 ml of water was added to the reaction mixture, and the mixture was stirred at room temperature for 0.5 h to separate an aqueous phase.
  • Step a Compound 11-a-1 (5 g, 31.6 mmol) was dissolved in 20 ml of sulfuric acid, cooled to 0 ° C, and added 1,3-dibromo-5,5-dimethylhydan (4.4 g, 15.5 mmol) Stir at 0 ° C for 2 h. After completion of the reaction, the mixture was poured into EtOAc EtOAc (EtOAc m.).
  • Step b To a solution of 11-a-2 (3 g, 12.7 mmol), methylsulfonamide (2.4 g, 25.4 mmol) in 300 ml of dichloromethane, HATU (2-(7-azobenzotriazole) -N,N,N',N'-tetramethyluron hexafluorophosphate) (7.2 g, 19.1 mmol), DIPEA (N,N-diisopropylethylamine) (3.3 g, 25.4 mmol), DMAP (4-Dimethylaminopyridine) (159 mg, 1.3 mmol), stirred at rt overnight.
  • HATU 2-(7-azobenzotriazole) -N,N,N',N'-tetramethyluron hexafluorophosphate
  • DIPEA N,N-diisopropylethylamine
  • DMAP 4-Dimethylaminopyridine
  • Step a Compound 13-a-1 (50 g, 0.40 mol) was added to concentrated hydrochloric acid (400 ml), and the mixture was cooled to 0 ° C, and a solution of sodium nitrite (28.6 g, 0.44 mol) in water (100 ml) was added dropwise. After the mixture was reacted at 0 ° C for 0.5 h, cuprous chloride (91.68 g, 0.48 mol) was added. After the mixture was stirred at room temperature for 0.5 h, it was heated to 100 ° C and stirred for 1 h.
  • Step c Compound 13-a-3 (9.1 g, 48 mmol) was dissolved in anhydrous DCM (150 mL), cooled to 0 <0> Imine hydrochloride (13.76 g, 72 mmol), DMAP (11.8 g, 96 mmol), methanesulfonamide (9.12 g, 96 mmol). After the mixture was stirred at room temperature for 18 h, EtOAc EtOAc m. Dry over anhydrous sodium sulfate and filter.
  • Step a To a solution of compound 17-a-1 (4.5 g, 28.8 mmol), p-toluenesulfonic acid (499 mg, 2.9 mmol) in dichloromethane (100 ml) The imide (4 g, 30.3 mmol) was stirred for 2 hours and stirred at room temperature overnight. After completion of the reaction, the mixture was poured into EtOAc EtOAc m. MS m / z (ESI): 189 [M-1] - .
  • Step b Concentrated sulfuric acid (7 ml, 1 mmol) was added dropwise to a solution of Compound 17-a-2 (5 g, 26.3 mmol) in methanol (130 ml). After the reaction was completed, it was cooled to room temperature, poured into water, EtOAc EtOAcjjjjjjjjj ). MS m / z (ESI): 203 [M-1] -.
  • Step a Refer to the preparation method of Step 3 in Example 57 using the compound 17-a (2 g) as a starting material, except that the reaction conditions were changed to room temperature and stirred overnight to obtain Compound 22-a-2 (552 mg), purity 96.57%. Yield 14%, MS m/z (ESI): 3221. [M+H-56] + .
  • Step b To a 50 ml single-necked round bottom flask was added compound 22-a-2 (552 mg), hydrochloric acid (4M, 5 ml, 20 mmol) The reaction was complete, the reaction was concentrated under reduced pressure to give a solid Compound 22-a (409mg), purity 100%, yield 41%, MS m / z ( ESI): 288 [M + H] +, was used directly in the next reaction.
  • Step a Using the compound 23-a-1 (1 g) as a starting material, the compound of the procedure of the step 2 in Example 29 gave Compound 23-a-2 (683 mg), purity 83.85%, yield 83%, MS m/z (ESI): 168.1 [M+H] + .
  • Step b To a solution of compound 23-a-2 (385 mg, 2.296 mmol) in acetonitrile (5 ml), p. (284 mg, 2.756 mmol), tetrabutylammonium bromide (1479 mg, 4.593 mmol), cuprous bromide (33 mg, 0.23 mmol). After completion of the reaction, the mixture was washed with EtOAc (EtOAc m.
  • the compound 24-a was prepared starting from the compound 4-bromoaniline and referring to the compound 23-a.
  • Step 1 To a 50 ml sealed tube was added 4-bromo-2-chloro-1-(trifluoromethoxy)benzene (215 mg, 0.781 mmol), compound 7-a (117 mg), Pd 2 (dba) 3 (3 (dibenzylideneacetone) dipalladium) (36 mg, 0.039 mmol), BINAP (( ⁇ )-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl) (51 mg, 0.082 mmol) ), potassium tert-butoxide (263 mg, 2.344 mmol), 7 ml of 1,4-dioxane, stirred at 90 ° C for 2 h.
  • Step 2 Compound 22-b (148.6 mg), 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide (107 mg, 0.397 mmol), cesium carbonate (260 mg, 0.798 mmol), A mixture of 6 ml of dimethyl sulfoxide was stirred at 220 ° C for 30 minutes under microwave conditions. After the reaction was completed, it was cooled to room temperature, 30 ml of water was added, the pH was adjusted to 6-7, ethyl acetate was extracted, and the organic phase was separated and concentrated under reduced pressure to give a crude oil (300 mg).
  • Compound Z-23 was prepared by the method of Example 22 using compound 7-a as a starting material, except that 4-bromo-2-chloro-1-(trifluoromethoxy)benzene was replaced in step 1. 4-bromo-1,2-dichlorobenzene.
  • Compound Z-28 was prepared by the method of Example 22 except that the compound 7-a in Step 1 was replaced with (S)-pyrrolidin-2-ylmethanol.
  • Compound Z-29 was prepared by the method of Example 22 except that the compound 7-a in Step 1 was replaced by (S)-pyrrolidin-2-ylmethanol, 4-bromo-2-chloro-1-(3) Fluoromethoxy)benzene is replaced by 4-bromo-1,2-dichlorobenzene.
  • Step 1 Compound 45-a (644 mg), hydrochloric acid (4M, 5 ml, 20 mmol) After completion of the reaction, the reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal
  • Step 2 Compound 33-b (425 mg) was used as the starting material.
  • the title compound was obtained from the title compound of Example 22 to give the compound 33-c (520 mg) as a yellow oil, purity 83.4%, yield 80.7%, MSm/z (ESI) :282[M+H] + .
  • Step 3 To a one-neck round bottom flask was added compound 33-c (288 mg, 1.0225 mmol), potassium tert-butoxide (344 mg, 3.065 mmol), THF 10 ml, and stirred for 2 min in ice-bath, and compound 1-a (358 mg, 1.327 mmol) ), stirring for 30 minutes. After completion of the reaction, water (10 ml x 3) and ethyl acetate (10 ml x 3) were added, and the combined organic phase was separated and concentrated under reduced pressure to give a crude product which was purified by liquid phase to give solid compound Z-33 (4.6 mg). The yield was 0.7%. MS m/z (ESI): 531 [M+H] + .
  • Step 1 1 -Bromo-4-(trifluoromethoxy)benzene (1 g, 4.15 mmol), compound 7-a (0.63 g, 6.22 mmol), (S)-valine (96 mg, 0.83 mmol), A mixed solution of cuprous iodide (79 mg, 0.415 mmol), potassium carbonate (1.72 g, 12.45 mmol) in dimethyl sulfoxide (10 ml) was stirred at 90 ° C for 4 h under nitrogen. After the reaction was completed, the mixture was cooled to room temperature, poured with water and ethyl acetate. EtOAc was evaporated.
  • Step 2 Compound 50-b (119 mg) was used as a starting material. [MH] - .
  • Compound Z-51 was prepared from compound 7-a using the procedure of Example 50, except that 1-bromo-4-(trifluoromethoxy)benzene in step 1 was replaced with 1-bromo- 2,4-Dichlorobenzene, the reaction conditions were changed to 140 ° C and stirred for 30 minutes.
  • Compound Z-52 was prepared starting from compound 7-a by the method of Example 50 except that the 1-bromo-4-(trifluoromethoxy)benzene in step 1 was changed to 4-bromo- 2-Chloro-1-fluorobenzene, the reaction conditions were changed to 90 ° C and stirred overnight.
  • Compound Z-56 was prepared from compound 7-a using the same procedure as in Example 50 except that 1-bromo-4-(trifluoromethoxy)benzene in step 1 was replaced with 4-bromo- 2-chlorobenzonitrile, and the reaction conditions were changed to 140 ° C and stirred for 30 minutes.
  • Compound Z-58 was prepared from compound 7-a using the same procedure as in Example 50 except that 1-bromo-4-(trifluoromethoxy)benzene in step 1 was replaced with 2-bromo- 5-chloropyridine, and the reaction conditions were changed to 110 ° C and stirred for 5 hours.
  • Compound Z-59 was prepared starting from compound 7-a by the method of Example 50 except that the 1-bromo-4-(trifluoromethoxy)benzene in Step 1 was changed to 3-bromo- 5-chloropyridine, and the reaction conditions were changed to 110 ° C and stirred overnight.
  • Compound Z-67 was prepared by the method of Example 50 using compound 7-a as a starting material, except that 1-bromo-4-(trifluoromethoxy)benzene in step 1 was replaced with 1-bromo- 4-(Trifluoromethyl)benzene, and the reaction conditions were changed to 100 ° C and stirred for 20 hours.
  • Compound Z-68 was prepared from compound 7-a using the procedure of Example 50, except that 1-bromo-4-(trifluoromethoxy)benzene in step 1 was replaced with 4-bromo- 1-Chloro-2-fluorobenzene, the reaction conditions were changed to 90 ° C and stirred for 8 hours.
  • Compound Z-69 was prepared from compound 7-a using the same procedure as in Example 50 except that 1-bromo-4-(trifluoromethoxy)benzene in step 1 was replaced with 4-bromo- 2-fluoro-1-(trifluoromethyl)benzene, and the reaction conditions were changed to 110 ° C and stirred overnight.
  • Compound Z-71 was prepared by the method of Example 50 using compound 7-a as a starting material, except that 1-bromo-4-(trifluoromethoxy)benzene in step 1 was changed to 5-bromo- 2-(Trifluoromethyl)pyridine, the reaction conditions were changed to 100 ° C and stirred overnight, and the reaction conditions of Step 2 were changed to 180 ° C and stirred for 30 minutes.
  • Compound Z-72 was prepared from compound 7-a using the procedure of Example 50, except that 1-bromo-4-(trifluoromethoxy)benzene in step 1 was replaced with 1-bromo- 4-(Trifluoromethyl)benzene, the reaction conditions were changed to 100 ° C and stirred for 20 hours. In the step 2, the compound 1-a was replaced with the compound 9-a, and the reaction conditions were changed to 200 ° C and stirred for 30 minutes.
  • the compound Z-76, Z-79 was prepared by the method of Example 50 using the compound 7-a as a starting material, except that the 1-bromo-4-(trifluoromethoxy)benzene in the step 1 was changed.
  • the compound 23-a, 24-a was added, and the reaction conditions were changed to 140 ° C for 30 minutes, and the reaction conditions in the step 2 were changed to 200 ° C for 30 minutes.
  • Step 1 Compound 22-b (504 mg, 1.704 mmol), p-toluenesulfonyl chloride (415 mg, 2.045 mmol), triethylamine (350 mg, 3.239 mmol), 4-dimethylaminopyridine (25 mg, 0.17 mmol)
  • the mixed solution of methyl chloride was stirred at room temperature for 6 hours. After the reaction was completed, a 1M aqueous solution of hydrochloric acid and sodium hydrogen carbonate solution was added, and the organic phase was separated and evaporated to give crude compound 53-b (754 mg).
  • Step 2 To a solution of compound 53-b (424 mg, 0.942 mmol) in EtOAc (EtOAc) The reaction was completed, cooled to room temperature, extracted with water and ethyl acetate. EtOAc was evaporated. The rate is 49%. MS m/z (ESI): 354.1 [M+H] + .
  • Step 3 Compound 53-c (150 mg) was used as a starting material to give the white solid compound Z-53 (144 mg), purity 96.65%, yield 38%, MS m/z ESI): 561 [M+H] + .
  • Step 1 The compound 22-b (200 mg) was used as a starting material, and the preparation method of the step 2 in Example 22 was used, except that the compound 1-a was replaced with the compound 11-a to give a white solid compound 54-b (110 mg). , purity 72%, yield 18.39%, MS m/z (ESI): 589 [M+H] + .
  • Step 2 Compound 54-b (100 mg, 0.17 mmol), cyclopropylboronic acid (29.13mg, 0.34mmol), potassium carbonate (46.87mg, 0.34mmol), palladium acetate (7.613mg, 0.034mmol), toluene (20ml) To the water (2 ml), tricyclohexylphosphine (47.55 mg, 0.17 mmol) was added, and the mixture was stirred at 100 ° C under nitrogen overnight. After completion of the reaction, the mixture was cooled to room temperature, washed with water and brine, and then evaporated. MS m/z (ESI): 552 [M+H] + .
  • Step 1 Compound 16-a (3 g, 13.7 mmol), methanesulfonamide (1.95 g, 20.5 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-four
  • HATU methyl urea hexafluorophosphate
  • triethylamine 2.77 mg, 27.4 mmol
  • dichloromethane 30 ml
  • Step 2 Compound 55-b (1 g, 3.38 mmol), zinc cyanide (237 mg, 2.03 mmol), tris(dibenzylideneacetone) dipalladium (31 mg, 0.034 mmol), 1,1'-bis(diphenyl)
  • Step 3 The compound 22-b (100 mg) was used as the starting material, and the procedure of the step 2 in Example 22 was used, except that the compound 1-a was changed to the compound 55-c to obtain the yellow solid compound Z-55 (44 mg). MS m/z (ESI): 518 [M+H] + .
  • Step 1 To a solution of compound 22-b (600 mg, 2.29 mmol) in dichloromethane (20 mL) After completion of the reaction, a sodium hydrogencarbonate solution, a sodium thiosulfate solution, methylene chloride solution, and a sodium hydrogencarbonate solution were evaporated, and the organic phase was separated and concentrated to give a crude yellow oily compound 57-b (575 mg). MS m/z (ESI): 294 [M+H] + .
  • Step 2 Methylmagnesium bromide (1 ml, 2.937 mmol) was added dropwise to a solution of compound 57-b (0.575 g, 1.58 mmol) in THF (5 ml). After the reaction was completed, the ammonium chloride solution was added, and ethyl acetate was evaporated. MS m/z (ESI): 310.1 [M+H] + .
  • Step 3 Add azo to a solution of compound 57-c (339 mg, 1.094 mmol), compound 17-a (224 mg, 1.094 mmol), triphenylphosphine (576 mg, 2.189 mmol) in toluene (5 ml) Diisopropyl diformate (443 mg, 2.189 mmol) was stirred under argon at 60 ° C overnight. After the reaction was completed, it was cooled to room temperature, poured into water, extracted with ethyl acetate, washed with brine, dried and evaporated. Purification by Combi-flash column chromatography gave compound 57-d (276 mg). MS m/z (ESI): 496.1 [M+H] + .
  • Step 5 To a 50 ml single-neck round bottom flask was added 3-chloro-4-(trifluoromethoxy)benzoic acid (31 g, 0.129 mmol), compound 57-e (87 mg), methanesulfonamide, HATU (2-( 7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate) (99 mg, 0.260 mmol), DIPEA (N,N-diisopropylethylamine) (56 mg, 0.433 mmol), 3 ml of dimethylformamide, stirred at room temperature overnight.
  • 3-chloro-4-(trifluoromethoxy)benzoic acid 31 g, 0.129 mmol
  • compound 57-e 87 mg
  • methanesulfonamide HATU (2-( 7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexaflu
  • Step 1 Using compound 7-a (2.92 g) as a starting material, the preparation was carried out according to the method of Example 50 except that the 1-bromo-4-(trifluoromethoxy)benzene in step 1 was changed to 4 -Bromo-2-chloro-1-(trifluoromethyl)benzene, and the reaction conditions were changed to 100 ° C and stirred for 16 hours.
  • the compound 60-b (2.076 g) was obtained as a yellow oil, which was used directly for the next reaction, purity 91.7%, yield 31%.
  • Step 2 To a solution of the compound 60-b (55 mg, 0.197 mmol) in THF (10 ml), EtOAc (EtOAc, EtOAc. Methyl), naturally warmed to room temperature and stirred for 2 hours. After completion of the reaction, ethyl acetate was extracted, and the aqueous solution was washed to pH 5-6. The organic phase was separated and purified by prep-HPLC to yield white solid compound Z-60 (22 mg). MS m / z (ESI): 511.1 [MH] - .
  • Step 1 Compound 7-a (6.08 g), 1-bromo-4-(trifluoromethyl)benzene (9 g, 40 mmol), 4,7-dimethoxy-1,10-phenanthroline (920 mg, 8 mmol), a mixed solution of cuprous iodide (764 mg, 4 mmol), potassium carbonate (16.56 g, 120 mmol) in dimethyl sulfoxide (20 ml), and stirred under argon atmosphere at 140 ° C for 30 min. After the reaction was completed, it was cooled to room temperature, poured into water, extracted with ethyl acetate, washed with brine, dried and evaporated. Purification by Combi-flash column chromatography gave a yellow oil, 81-b (3.98 g).
  • Step 2 Compound 81-b (956 mg) was used as a starting material. m. ] + .
  • Step 3 Compound 81-c (1.1 g) was used as a starting material, m m m m m m m m m m m m m m H] + .
  • Step 4 Compound 81-d (100 mg) and ethanesulfonamide (52 mg) were used as the starting material, and the compound of the compound b-81 (50 mg), MS m/z ESI): 509.2 [M+H] + .
  • 5-chloropyrimidine, 4-bromopyrimidine, 2-bromo-5-(trifluoromethyl)pyridine, and the ethanesulfonamide in step 4 is replaced with methylsulfonamide or isopropanesulfonamide, respectively.
  • Step 1 Using compound 7-a (728 mg) as a starting material, followed by the procedure of Example 1 Step 50, except that 1-bromo-4-(trifluoromethoxy)benzene was replaced by 4-bromo- 2-Chloro-l-fluorobenzene, and the reaction mixture was stirred at 90 ° C overnight to afford compound 63-b (120 mg), MS m/z (ESI): 230 [M+H] + .
  • Step 2 The compound 63-b (110 mg) was used as a starting material, and the preparation was carried out in the same manner as in the step 2 of Example 22 except that the compound 1-a was replaced with the compound 11-a, and the reaction conditions were changed to 180 ° C. After stirring for 1 hour, a white solid compound 63-c (120 mg), MS m/z (ESI): 503 [M+H] + .
  • Step 3 To a solution of compound 63-c (130.5 mg), cyclopropylboronic acid (43 mg, 0.5 mmol) in 10 ml of dioxane, [1,1'-bis(diphenylphosphino)ferrocene] Palladium chloride (22 mg, 0.03 mmol), cesium carbonate (163 mg, 0.5 mmol), argon, and stirred at 100 ° C overnight. After the reaction was completed, it was cooled to room temperature, filtered, and poured into water, and ethyl acetate was evaporated. MS m/z (ESI): 495 [M+H] + .
  • Compound Z-65 was prepared according to the method of Example 63, starting from compound 7-a, except that 4-bromo-2-chloro-1-fluorobenzene was replaced with 1-bromo-4- in step 1. chlorobenzene.
  • Compound Z-73 was prepared according to the method of Example 63, starting from compound 7-a, except that 4-bromo-2-chloro-1-fluorobenzene was replaced with 1-bromo-4- in step 1. (Trifluoromethyl)benzene, the reaction conditions were changed to 100 ° C for 16 hours, the reaction conditions of the step 2 were changed to 200 ° C for 30 minutes, and the reaction conditions of the step 3 were changed to 80 ° C for 16 hours.
  • Step 1 2-Chloro-6-fluoropyridine (2.20 g, 16.72 mmol), compound 7-a (1.27 g, 12.54 mmol), potassium carbonate (2.31 g, 16.72 mmol) in dimethylformamide (22 ml) The solution was stirred at 80 ° C for 5 hours. After completion of the reaction, the mixture was cooled to room temperature, poured into water, extracted with ethyl acetate, washed with water, brine, and evaporated. Purification by Combi-flash column chromatography gave yellow solid compound 64-b (2 g). MS m/z (ESI): 213 [M+H] + .
  • Step 2 Starting from the compound 64-b (500 mg), which was obtained by the procedure of Step 2 of Example 22, except that the reaction conditions were changed to 200 ° C for 1 hour to obtain a white solid compound Z-64 (80 mg). MS m/z (ESI): 462 [M+H] + .
  • Compound Z-70 was prepared according to the method of Example 64 using compound 7-a as a starting material, except that 2-chloro-6-fluoropyridine in step 1 was replaced by 2-bromo-5-(trifluoromethyl). The pyridine was subjected to the reaction conditions in the step 2 and stirred at 180 ° C for 30 minutes.
  • Step 1 To a solution of compound 20-a (1.5 g, 7.128 mmol), EtOAc (EtOAc:EtOAc (EtOAc) A solution of tetrahydrofuran (20 ml) was stirred at room temperature for 1 h. After the reaction was completed, water was added, the organic phase was separated, and the organic phase was separated, and the organic layer was evaporated. One-step reaction, purity 99.01%, yield 89%. MS m/z (ESI): 250 [M+H] + .
  • Step 2 The compound 7-a (407 mg) was used as a starting material, which was prepared by the method of Step 1 of Example 50, except that 1-bromo-4-(trifluoromethoxy)benzene was replaced in the step.
  • compound 66-b, 95 deg.] C into the reaction conditions stirred overnight to give a white solid compound 66-c (194mg), MS m / z (ESI): 269.1 [m + H] +.
  • Step 3 Starting from the compound 66-c (164 mg), which was obtained by the procedure of Step 2 of Example 22, except that the reaction conditions in the step were changed to 200 ° C for 30 minutes to obtain a white solid compound Z-66. (33.06mg), MS m / z (ESI): 518.1 [m + H] +.
  • Step 1 Using compound 7-a (6.08 g) as a starting material, followed by the procedure of Step 1 of Example 50, except that 1-bromo-4-(trifluoromethoxy)benzene was replaced in the step. 1-Bromo-4-(trifluoromethyl)benzene, mp. + .
  • Step 2 The compound 82-b (490 mg) was used as a starting material, and the preparation of the compound in the step of step 57 was carried out, except that the compound 17-a was replaced with the compound 25-a, and the reaction conditions were changed to room temperature stirring. 2 hours to obtain a colorless oil compound 82-c (650mg), MS m / z (ESI): 478.1 [m + H] +.
  • Step 3 The compound 82-c (650 mg) was used as a starting material, and the mixture was subjected to the procedure of Step 4 of Example 57, except that the reaction conditions were changed to 60 ° C and stirred for 2 hours to obtain a white solid compound 82-d (509 mg).
  • Step 4 Compound 82-d (500 mg) was used as a starting material to give a white solid compound 82-e (150 mg), MS m/z (ESI): 539 [M+H ] + .
  • Step 5 Compound 82-e (50 mg, 0.093 mmol), methylboronic acid (7 mg, 0.111 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride (7 mg, 0.009) Methyl acetate (30 mg, 0.278 mmol) in dioxane (15 ml) mixture was stirred at 100 ° C overnight. After completion of the reaction, the mixture was cooled to room temperature, filtered, and the filtrate was evaporated. MS m/z (ESI): 475.2 [M+H] + .
  • step 4 replacing the methylsulfonamide in step 4 with ethanesulfonamide, cyclopropanesulfonamide or isopropanesulfonamide, respectively, or replacing methylboric acid in step 5 with Ethyl boric acid, isopropyl boric acid, cyclopropyl boric acid.
  • the compound Z-84 was prepared by the method of Example 82 using the compound 82-e as a starting material, except that the methylboronic acid in the step 5 was replaced with phenylboronic acid, and the reaction conditions were changed to 100 ° C under argon gas for 4 hours. .
  • Step 1 The compound 82-b (250 mg) was used as a starting material, and the preparation was carried out by the method of Step 3 of Example 57 except that the compound 17-a was replaced with the compound 25-a-1 in the step, and the reaction conditions were changed. was stirred at room temperature for 2 hours to give a yellow oil compound 83-c (373mg), MS m / z (ESI): 398.2 [m + H] +.
  • Step 2 Preparation of Compound 83-c (373 mg), m. m. H] + .
  • Step 3 Using compound 83-d (100 mg) as a starting material, a mixture of compound 83-d (49 mg), methanesulfonamide (65 mg, 0.181 mmol), HATU (2-(7-even) was added to a 50 ml single-neck round bottom flask. Nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate) (99 mg, 0.260 mmol), DIPEA (N,N-diisopropylethylamine) (56 mg, 0.433 mmol), 3 ml of dimethylformamide, stirred at room temperature overnight.
  • Step 1 Using the compound (R)-tert-butyl-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.19 g) as a starting material, referring to the preparation method of the step 2 in Example 22, the reaction conditions were used. The mixture was stirred for 20 minutes at 180 ° C to give compound 77-b (375 mg), MS m/z (ESI): 351 [M+H-100] + .
  • Step 2 Compound 77-b (169 mg), hydrochloric acid (4M, 2 ml, The reaction was complete, the reaction was concentrated under reduced pressure to give 77-c (54mg), MS m / z (ESI): 351 [M + H-36] +, was used directly in the next reaction,
  • Step 3 To a 50 ml single-neck round bottom flask was added 4-chlorobenzoic acid (16 mg, 0.102 mmol), compound 77-c (40 mg, 0.102 mmol), 2-(7-azobenzotriazole)-N, N,N',N'-tetramethyluronium hexafluorophosphate (118 mg, 0.306 mmol), N,N-diisopropylethylamine (40 mg, 0.306 mmol), m. The reaction was completed, and ethyl acetate and water were extracted, and the organic layer was separated, and concentrated under reduced pressure, and purified by preparative liquid phase to give compound C1 (5.26 mg), purity 92%, yield 10%.
  • Compound C2 was prepared starting from compound 77-c using the method of Comparative Example 1, except that the 4-chlorobenzoic acid in Step 3 was changed to 4-(trifluoromethyl)benzoic acid.
  • Step 1 To a solution of Compound 21-a (174 mg) in EtOAc (EtOAc) After completion of the reaction, the ammonium chloride solution was added, and the mixture was evaporated to dichloromethane.
  • Step 2 To a solution of the compound 74-b (182 mg) and EtOAc (EtOAc) After completion of the reaction, the mixture was washed with EtOAc EtOAc.
  • Step 3 Compound 74-c (124 mg, 0.563 mmol), Compound 22-a (162 mg, 0.563 mmol), EtOAc ( EtOAc, EtOAc After the reaction was completed, it was cooled to room temperature, washed with water, and then dried and evaporated. Purification by Combi-flash column chromatography gave compound 44-d (147 mg). MS m/z (ESI): 412 [M+H] + .
  • Step 4 Compound 74-d (147 mg) H] + .
  • Step 5 Compound 74-e (97 mg) was used as a starting material to give Compound Compound C3 (21.04mg), MS m/z (ESI): 475.1 [M+H] + .
  • Compound C4 was prepared by the method of Comparative Example 3 using the compound 4-(trifluoromethyl)benzaldehyde as a starting material.
  • Step 1 Compound Z-0-1 (20.0 g, 155 mmol) was dissolved in tert-butanol (150 mL), cooled to 0 ° C, diphenyl azide (47 g, 170 mmol), triethylamine (17.3 g, 170 mmol). The mixture was stirred at reflux for 18 h and then dried with a rotary evaporator. The residue was dissolved in dichloromethane (400 mL) and washed with water (200 ⁇ RTIgt; Dry over anhydrous sodium sulfate and suction filtration.
  • Step 2 Dissolve Z-0-2 (8.0 g, 0.04 mol) in dry THF (80 mL) under N 2 and then cooled to -78 ° C and then add dropwise LiHMDS (1M, 48ml, 0.048 mol) THF solution. After the dropwise addition was completed, the mixture was stirred at -78 ° C for 0.5 h. The reaction solution was slowly warmed to room temperature, stirred for 1 h, then cooled to -78 ° C, and a solution of 5-chloro-2,4-difluorobenzenesulfonyl chloride (11.11 g, 0.048 mol) in THF (50 ml) was added dropwise. The reaction solution.
  • Step 3 Compound Z-0-4 (50.8 g, 254 mmol) was dissolved in THF (600 mL). After the mixture was stirred at 0 ° C for 2 h, the reaction was quenched with water and then EtOAc (EtOAc) (EtOAc). The filtrate was triturated with a rotary evaporator to give a white solid, Z-0-5 (32.0 g, yield: 73.5%).
  • Step 4 Compound Z-0-5 (32.0 g, 190 mmol) was dissolved in dichloromethane (400 mL) and then th The mixture was heated to reflux with stirring for 3 h under nitrogen. The mixture was cooled to room temperature and then quenched with water (20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium The filtrate was dried with a rotary evaporator to give a red solid, Z-0-6 (33.0 g, yield: 92.2%).
  • Step 5 Compound Z-0-6 (32 g, 168 mmol) was dissolved in DMSO (200 mL) and sodium cyanide (29 g, 606 mmol). The mixture was heated to 80 ° C under nitrogen for 3 h. The reaction mixture was cooled to room temperature, added with water and filtered. The filter cake was washed with a small amount of water. It was dried to an orange solid Z-0-7 (31 g, yield: 98.3%).
  • Step 7 Compound Z-0-8 (10.5 g, 50.2 mmol) was dissolved in ethanol (150 mL) and tert-butyl hydrazine (7.5 g, 60.3 mmol) was added. The mixture was heated under reflux with stirring for 3.5 h. The reaction mixture was cooled to room temperature and evaporated to dryness crystals crystals crystals
  • Test Example 1 manual patch clamp experiment of hNav1.7 and hNav1.5 channels
  • Diaphragm voltage clamp electrophysiology can directly measure and quantify current blockade of voltage-gated sodium channels (various Nav) and can determine the time and voltage dependence of blockade, which has been interpreted as resting, open and sodium channels The difference in binding in the inactive state reflects the inhibitory or activating effect of the compound (Hille, B., Journal of General Physiology (1977), 69: 497-515).
  • Representative compounds of the invention were tested using a manual patch clamp experiment.
  • the purpose of this study was to test the effect of compounds on the ion channel current on a stable cell line transfected with a particular ion channel using a manual patch clamp method.
  • the stable cell lines CHO-hNav1.7 and HEK-hNav1.5 used were from Genionics and WuXi Apptec (Shanghai), respectively.
  • the manual patch clamp experimental protocol is as follows:
  • the positive control drug and the test compound were first dissolved in 100% DMSO (Sigma-Aldrich, D2650, and stored in a certain concentration (100 nM, 1000 nM) stock solution.
  • DMSO Sigma-Aldrich, D2650
  • the above stock solution was serially diluted with DMSO before the experiment, and then used outside the cell.
  • the solution is further diluted to give the test solution at the desired concentration.
  • the final concentration of DMSO in the extracellular fluid does not exceed 0.30%.
  • This stimulation procedure can also be referred to as a channel state dependent voltage stimulation procedure.
  • the other is a non-inactivation stimulation program that maintains the clamp potential at -120 mV, gives a voltage stimulus to -10 mV, continues for 20 ms to draw sodium current, and finally returns to the clamp potential. That is to say, under the conditions of the stimulation program, all the channels have not experienced the inactivation state, but are directly activated from the resting state.
  • the time interval of the above two voltage stimulation programs is 10s.
  • the inhibitory effect of the compound was calculated by the change in current before and after dosing, and the IC 50 value was fitted by the Hill equation.
  • a compound is state dependent on the channel if it exhibits a multiple of the channel effect under the two different voltage stimuli described above. The results are shown in Tables 1 and 2, respectively.
  • the different substitution positions on the pyrrole ring carbon have a significant effect on the selectivity.
  • the selectivity of the 2-substituted compound is significantly improved over the selectivity of the 3-substituted compound.
  • the nitrogen atom is not directly connected to the A ring (such as a benzene ring or a pyridine ring), that is, the ring A (such as a benzene ring or a pyridine ring) is bonded to the nitrogen atom through a group such as a methylene group or a carbonyl group, the inhibition is performed. There is a significant decrease in activity.
  • the experimental animals were male Sprague-Dawley rats with a body weight of 140-150 g at the start of the experiment.
  • the experimental animals were purchased from Slack Company. After purchase, the food and water supply were carried out in a free-feeding manner. They were kept in cages, 4 cages, and the animals were labeled with animal tail marking.
  • HYC00012 also known as compound Z-0
  • Drug to be tested compound Z-22, Z-40, Z-47, Z-54, Z-73;
  • the solvent composition of the positive control and the drug to be tested is 5% dimethylacetamide, 5% solutol and 90% raw. Salt water.
  • the positive control and the test substance inhibited the cold pain hypersensitivity caused by spinal nerve ligation in rats after oral administration for 2 hours at a dose of 100 mg/kg, respectively, as shown in Table 4.
  • 100mg/kg positive control Z-0 Weighed 278.6mg positive control, added 0.68mL dimethylacetamide, added 0.68mL solutol after complete dissolution, shake and mix, add 90% physiological saline to volume to 13.52mL , orally administered after complete dissolution.
  • the rats were subjected to a cold hyperalgesia hypersensitivity baseline test, and 100 ⁇ l of acetone was applied to the hind paw skin of the animal side using a pipette. Record the time the animal patted, retracted, lifted, and licked the foot in one minute. The acetone test was performed twice in total, 10 minutes apart. The sum of the two times was recorded as the time of cold allodynia hypersensitivity in rats. Animals were randomized according to the results of the cold allodynia hypersensitivity test one day prior to dosing.
  • acetone was applied to the skin of the toes of the animal side using a pipette. Record the time the animal pats, shrinks, lifts, and affects the affected foot in one minute. The acetone test was performed twice in total, 10 minutes apart. The sum of the two times was recorded as the time of cold allodynia hypersensitivity in rats.
  • the cold stimulating pain test was orally administered 2 hours before.
  • compound Z-40 inhibits cold-stimulated hyperalgesia in a rat model of spinal nerve ligation, *p ⁇ 0.05, *** p ⁇ 0.001.
  • a Dunnett multiple comparison test was added using one-way ANOVA compared to the solvent group.
  • Oral compound Z-40 and the positive control 100 mg/kg inhibited cold allodynia hypersensitivity induced by spinal nerve ligation in rats two hours later.
  • Test Example 4 In vivo test in rats
  • the drug concentration in plasma at different times after administration of the compound of the example by intragastric administration was determined by LC/MS/MS method.
  • the pharmacokinetic behavior of the compound of the present invention in rats was investigated, and its pharmacokinetic characteristics were evaluated.
  • Test animals healthy adult male SD rats (body weight 200-300 g, 6 rats, fasted), provided by Slark;
  • Blood sample collection First, select the animals that meet the experimental requirements before the administration, and weigh the markers. Before the blood sample is collected, the rats are bound, and each rat is administered at a predetermined blood collection time point (administered by gavage: 0.083, 0.25, 0.5, 1, 2, 4 after administration, respectively, before administration). , 8, 24h blood collection, a total of 9 time points), blood collection through the tail vein, about 150 ⁇ L. The blood was transferred to a 1.5 mL tube pre-added to K 2 EDTA. The collected blood samples were placed on wet ice, centrifuged for 5 min (2000 g, 4 ° C), and the plasma was taken out. The whole process was completed within 15 min after blood collection. All samples need to be stored in a -70 ° C refrigerator until sample analysis.
  • the drug concentration was determined by LC/MS/MS method.
  • the pharmacokinetic properties of the compounds in some embodiments of the present invention in the same mode of administration are shown in Table 10:
  • the exemplified compounds of the present invention have good pharmacological absorption, have significant pharmacological absorption effects, and exhibit better bioavailability (better than control compounds such as C5).
  • the compound of the present invention represented by Z-73 has more excellent properties and can be administered at a lower dose, so that it is safer or more toxic. The side effects are lower.

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Abstract

本发明公开了杂环取代的N-磺酰基苯甲酰胺衍生物、其制法与医药上的用途。具体地，本发明公开了式（II）化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药，及其制备方法和应用，式中各基团的定义详见说明书。

Description

杂环取代的N-磺酰基苯甲酰胺衍生物、其制法与医药上的用途 技术领域
本发明属于医药技术领域。具体地，本发明特别涉及一种杂环取代的N-磺酰基苯甲酰胺衍生物及其制备方法和作为钠离子通道(特别是Nav1.7)抑制剂的应用，以及由其制备的药物组合物和药用组合物。
背景技术
最近，英国的Cox等在Nature上首次报道了编码电压门控Nav1.7通道的SCN9A基因突变导致遗传个体无痛症的出人意料研究结果。该遗传突变的个体先天失去痛觉，但机体的其它功能完全正常，此外最近的研究表明，表达在DRG神经元的电压门控Nav1.7通道参与痛信号的产生并发挥控制痛觉信号传入的闸门功能。该研究提示Nav1.7通道可能会成为选择性治疗疼痛并无副作用的药物靶点。
Nav1.7(PN1，SCN9A)VGSC对河豚毒素的阻断敏感，其主要表达于末梢交感神经元和感觉神经元。SCN9A基因已由多种物种(包括人类、大鼠及兔)复制，并且显示人与大鼠基因之间的氨基酸有约90％的一致性。
越来越多的身体证据表明Nav1.7在多种疼痛状态(包括急性、慢性、炎性和/或神经性疼痛)中扮演重要的角色，在人类中，Nav1.7蛋白质积累于神经瘤，特别是引起疼痛的神经瘤。Nav1.7功能增加的突变(不论是遗传性或偶发性)已被认为涉及原发性红斑性肢痛(一种特征为四肢的灼痛和发炎的疾病)，和突发性极度疼痛症。有关非选择性钠通道阻断剂利多卡因和美西律可缓和遗传性红斑性肢痛的症状，以及卡马西平可有效地减低PEPD的侵袭的次数和严重度的报道结果与上述观察相一致。Nav1.7在疼痛中扮演的角色的其他证据可见于SCN9A基因的功能丧失的突变的显型。后续的研究已显示会导致SCN9A基因的功能丧失与CIP显型的许多不同的突变。
由于Nav1.7特异地在DRG感觉神经元表达而不在心肌细胞和中枢神经系统等其它组织表达，因此研发其特异阻断剂用于治疗慢性痛，不仅可能提高疗效，且副作用也会大大减少，并且Nav1.7离子通道的选择性抑制剂几乎可用于各种疼痛的治疗。
由于患急性或慢性疼痛疾病的许多患者对目前疼痛疗法响应较差，并且通常对阿片制剂产生抗性和不敏感性。此外，目前使用的钠通道阻断剂对于上述疾病 状况的功效在很大程度上受许多副作用的限制。这些副作用包括各种CNS紊乱，比如视力模糊、眩晕、恶心和镇静，以及更潜在地威胁生命的心律失常和心力衰竭。
因此，鉴于目前可用药剂有限的效力和不可接受的副作用，迫切需要开发更加安全有效的镇痛药，使其具有较高功效和较少副作用。而Nav1.7离子通道是开发无成瘾性镇痛药物的重要靶标，Nav1.7离子通道高度选择性抑制剂可用于广泛的疼痛治疗，因此开发新型Nav1.7离子通道高度选择性抑制剂十分必要。
发明内容
本发明的目的是提供一种Nav1.7离子通道高度选择性抑制剂及其在医药上应用。
本发明的第一方面提供了一种式(II)所示的化合物，或其药学上可接受的盐、溶剂化物、立体异构体或前药：
Figure PCTCN2016073387-appb-000001
式中，R1、R2、R3、R4各自独立地为氢、羟基、CN、NO2、卤素、-NRaRb、C1-20烷基、C3-20环烷基、C3-20环烷氧基、C2-20烯基、C2-20炔基、C1-20烷氧基、-CHO、-CO-(C1-20烷基)、-CO-(C6-20芳基)、C6-20芳基、-CONRaRb、-C(O)O-(C1-20烷基)、-OC(O)-(C1-20烷基)、-SO2-(C1-20烷基)或-SO2-(C6-20芳基)；
R5为氢、C1-20烷基、C3-20环烷基、卤代C1-20烷基；
R6为C6-20芳基、C1-20烷基、-NRaRb；其中，Ra、Rb各自独立地为氢、C1-20烷基、C3-20环烷基或C6-20芳基；
L1连接在环上的任意不同的位置，为一个键、或-C(O)N(Ry)-、-N(Ry)C(O)-、-N(Ry)SO2-、-SO2N(Ry)-、-OC(O)-、-C(O)O-、-(CRyRx)r1(O)r2(CRyRx)r3-、-S(O)-、-SO2-、-N(Ry)-、-O-、-S-、-C(O)-或亚环丙基；其中，Ry、Rx各自独立地为氢、卤素、羟基、CN、NO2、C1-20烷基、卤代C1-20烷基、C3-20环烷基、C2-20烯基、C2-20炔基或C6-20芳基；r1、r3各自独立地为0、1、2或3；r2为0或1；
W1、W2各自独立地为C、N、O或S；
n、m各自独立地为0、1、2或3，且n、m不同时为0；其中，当n为0时或m 为0时，W1和W2之间通过单键相连；
(R0)p为环上的任意位置的氢被p个R0取代，p为0、1、2、3、4或5，每个R0相同或不同，各自独立地为氢、氘、C1-20烷基、氘代C1-20烷基或卤代C1-20烷基；或任意两个R0通过单键或-(CH2)p1-连接，p1为1、2或3；
A为C6-20芳基、3至7元单环、8至10元双环、3至7元单杂环、8至10元双杂环、5或6元单环杂芳基环、8至10元双环杂芳基环、苯并3至7元单环、苯并3至7元单杂环、5至6元单环杂芳基环并3至7元单环、5至6元单环杂芳基环并3至7元单杂环；
其中，所述烷基、环烷基、环烷氧基、烯基、炔基、烷氧基、芳基、3至7元单环、8至10元双环、3至7元单杂环、8至10元双杂环、5或6元单环杂芳基环、8至10元双环杂芳基环、苯并3至7元单环、苯并3至7元单杂环、5至6元单环杂芳基环并3至7元单环、或5至6元单环杂芳基环并3至7元单杂环为取代的或未取代的；且所述的取代是指基团中的1-5个氢被选自下组的取代基所取代：卤素、硝基、羟基、氰基、C6-20芳基、C1-20烷基、卤代C1-20烷基、C1-20烷氧基、卤代C1-20烷氧基、C3-20环烷基、卤代C3-20环烷基、C3-20环烷氧基、卤代C3-20环烷氧基、C2-20烯基、卤代C2-20烯基、C2-20炔基、卤代C2-20炔基、C1-20烷硫基、卤代C1-20烷硫基、C1-20烷基氨基、卤代C1-20烷基氨基、硫醇、3元至20元的杂环烷基、3元至20元的杂环烷基氧基、C3-20环烷硫基、卤代C3-20环烷硫基、3元至20元的杂环烷基硫基、氧代基、C1-20羟烷基、羧基、-NRaRb、-C(O)NRaRb、-N(Ra)C(O)-(C1-20烷基)、-N(Ra)SO2-(C1-20烷基)、-SO2N(RaRb)、-C(O)O-(C1-20烷基)、-CHO、-OC(O)-(C1-20烷基)、-SO2-(C1-20烷基)、-SO2-(C6-20芳基)、-CO-(C6-20芳基)；Ra、Rb各自独立地为氢、C1-20烷基、C3-20环烷基或C6-20芳基；
并且，
Figure PCTCN2016073387-appb-000002
选自：
Figure PCTCN2016073387-appb-000003
Figure PCTCN2016073387-appb-000004
或
Figure PCTCN2016073387-appb-000005
其中，A、L1、R0如上所定义。
在另一优选例中，W1为N、O、S或C，当W1为O或S时，L1与环上除W1和W2以外的其它任意碳原子连接，当W1为N或C时，L1与环上除W2以外的其它任意环原子连接，较佳地，L1与W1连接。
在另一优选例中，每个R0相同或不同，各自独立地为氢。
在另一优选例中，A为C6-20芳基或5或6元单环杂芳基环。
在另一优选例中，A为苯基或吡啶基；所述的苯基或吡啶基为取代的或未取代的；且所述的取代是指基团中的1-5个氢被选自下组的取代基所取代：卤素、C1-20烷基、卤代C1-20烷基、C1-20烷氧基、卤代C1-20烷氧基、C3-20环烷基、和C3-20环烷氧基。
在另一优选例中，L1为一个键、或-(CRyRx)r1(O)r2(CRyRx)r3-；其中，Ry、Rx各自独立地为氢；r1、r3各自独立地为0、1、2或3；r2为0或1。
在另一优选例中，L1为-(CRyRx)r1(O)r2(CRyRx)r3-；其中，Ry、Rx各自独立地为氢；r1为1或2；r2为1；r3为0或1。
在另一优选例中，所述化合物为式(III)所示化合物：
Figure PCTCN2016073387-appb-000006
式中，R0、R1、R2、R3、R4、R5、R6、Rx、Ry、r1、r2、r3、A、W1、W2、n、p、m如上所定义。
在另一优选例中，式(III)化合物中，W1为N、O、S或C，当W1为O或S时，(CRyRx)r1与环上除W1和W2以外的其它任意碳原子连接，当W1为N或C时，(CRyRx)r1与环上除W2以外的其它任意环原子连接，r1如上所定义。
在另一优选例中，W2为N。
在另一优选例中，W1为N、O、S或C。
在另一优选例中，A为
Figure PCTCN2016073387-appb-000007
其中R1’、R2’、R3’、R4’、R5’如说明书中所定义。
在另一优选例中，A为
Figure PCTCN2016073387-appb-000008
或
Figure PCTCN2016073387-appb-000009
其中R21、R31、R41、R51、R12、R32、R42、R52、R13、R23、R43、R53各自独立地为氢、卤素、硝基、羟基、氰基、C6-20芳基、C1-20烷基、卤代C1-20烷基、卤代C1-20烷 氧基、C1-20烷氧基、C3-20环烷基、卤代C3-20环烷基、C3-20环烷氧基、卤代C3-20环烷氧基、C2-20烯基、卤代C2-20烯基、C2-20炔基、卤代C2-20炔基、-NRaRb、-C(O)NRaRb、-N(Ra)C(O)-(C1-20烷基)、-N(Ra)SO2-(C1-20烷基)、-SO2N(RaRb)、-C(O)O-(C1-20烷基)、-CHO、-OC(O)-(C1-20烷基)、-SO2-(C1-20烷基)、-SO2-(C6-20芳基)、-CO-(C1-20烷基)、-CO-(C6-20芳基)；Ra、Rb如上所定义。
在另一优选例中，
Figure PCTCN2016073387-appb-000010
选自：
Figure PCTCN2016073387-appb-000011
和
Figure PCTCN2016073387-appb-000012
其中，A、L1、R0如上所定义。
在另一优选例中，所述化合物为式(IV)所示化合物：
Figure PCTCN2016073387-appb-000013
式中，R0、R1、R2、R3、R4、R5、R6、Rx、Ry、r1、r2、r3、A、W2、n、p、m定义如前；W1为N或C。
在另一优选例中，r2为0。
在另一优选例中，r1、r3为0；r2为1。
在另一优选例中，r1为1、2或3；r2为1；r3为0。
在另一优选例中，r1为1；r2为1；r3为0。
在另一优选例中，r1为0；r2为1；r3为1、2或3。
在另一优选例中，r1、r2、r3为0。
在另一优选例中，所述化合物为式(V)所示化合物：
Figure PCTCN2016073387-appb-000014
式中，R0、R1、R2、R3、R4、R5、R6、L1、W1、W2、n、p、m定义如前；R1’、R2’、R3’、R4’、R5’各自独立地为氢、卤素、硝基、羟基、氰基、C6-20芳基、C1-20 烷基、卤代C1-20烷基、卤代C1-20烷氧基、C1-20烷氧基、C3-20环烷基、卤代C3-20环烷基、C3-20环烷氧基、卤代C3-20环烷氧基、C2-20烯基、卤代C2-20烯基、C2-20炔基、卤代C2-20炔基、-NRaRb、-C(O)NRaRb、-N(Ra)C(O)-(C1-20烷基)、-N(Ra)SO2-(C1-20烷基)、-SO2N(RaRb)、-C(O)O-(C1-20烷基)、-CHO、-OC(O)-(C1-20烷基)、-SO2-(C1-20烷基)、-SO2-(C6-20芳基)、-CO-(C1-20烷基)、-CO-(C6-20芳基)；Ra、Rb如上所定义。
在另一优选例中，R1’、R2’、R3’、R4’、R5’各自独立地为氢、卤素、C1-20烷基、卤代C1-20烷基、卤代C1-20烷氧基、C1-20烷氧基、C3-20环烷基、C3-20环烷氧基。
在另一优选例中，R21、R31、R41、R51、R12、R32、R42、R52、R13、R23、R43、R53各自独立地为氢、卤素、C1-20烷基、卤代C1-20烷基、卤代C1-20烷氧基、C1-20烷氧基、C3-20环烷基、C3-20环烷氧基。
在另一优选例中，式(V)化合物中，L1为-(CRyRx)r1(O)r2(CRyRx)r3-，r1、r2、r3如上所定义。
在另一优选例中，式(V)化合物中，W1为N、O、S或C，当W1为O或S时，L1与环上除W1和W2以外的其它任意碳原子连接，当W1为N或C时，L1与环上除W2以外的其它任意环原子连接，较佳地，L1与W1连接。
在另一优选例中，式(V)化合物中，W2为N。
在另一优选例中，R1、R2、R3、R4各自独立地为氢、卤素、C1-20烷基、C3-20环烷基；
R5为氢；
R6为C1-20烷基、-NRaRb；
其中，Ra、Rb各自独立地为氢、或C1-20烷基；
W1、W2各自独立地为C、O、S或N；
L1为一个键、或-(CRyRx)r1(O)r2(CRyRx)r3-、-O-或-C(O)-；其中，Ry、Rx各自独立地为氢；r1、r3各自独立地为0或1；r2为0或1；
n、m各自独立地为1或2；
(R0)p为环上的任意位置的氢被p个R0取代，p为0；
A为苯基；
且当W1和/或W2为O或S时，L1和A分别与环上除W1和W2以外的其它任意碳原子连接；
当W1和/或W2为N或C时，A与环上除W1以外的其它任意环原子连接，L1与 环上除W2以外的其它任意环原子连接；和/或
其中，所述烷基、环烷基或苯基为取代的或未取代的；且所述的取代是指基团中的1-5个氢被选自下组的取代基所取代：卤素、C1-20烷基、卤代C1-20烷基、C1-20烷氧基、卤代C1-20烷氧基。
在另一优选例中，R2和R4为氢，且R1、R3各自独立地为卤素、C3-6环烷基、C1-3烷基、C3-6环烷氧基或C1-3烷氧基。
在另一优选例中，所述式(II)-(V)所示化合物中，
R1、R2、R3、R4各自独立地为氢、卤素、C1-20烷基、C3-20环烷基；
R5为氢；
R6为C1-20烷基、-NRaRb；其中，Ra、Rb各自独立地为氢、C1-20烷基；
Figure PCTCN2016073387-appb-000015
选自：
Figure PCTCN2016073387-appb-000016
或
Figure PCTCN2016073387-appb-000017
A为C6-20芳基或5或6元单环杂芳基环；
L1为一个键、或-(CRyRx)r1(O)r2(CRyRx)r3-；其中，Ry、Rx各自独立地为氢；r1、r3各自独立地为0、1、2或3；r2为0或1；
每个R0相同或不同，各自独立地为氢；
所述烷基、环烷基、芳基、5或6元单环杂芳基环为取代的或未取代的；且所述的取代是指基团中的1-5个氢被选自下组的取代基所取代：卤素、硝基、羟基、氰基、C6-20芳基、C1-20烷基、卤代C1-20烷基、C1-20烷氧基、卤代C1-20烷氧基、C3-20环烷基、卤代C3-20环烷基、C3-20环烷氧基、卤代C3-20环烷氧基、C2-20烯基、卤代C2-20烯基、C2-20炔基、卤代C2-20炔基、C1-20烷硫基、卤代C1-20烷硫基、C1-20烷基氨基、卤代C1-20烷基氨基、硫醇、3元至20元的杂环烷基、3元至20元的杂环烷基氧基、C3-20环烷硫基、卤代C3-20环烷硫基、3元至20元的杂环烷基硫基、氧代基、C1-20羟烷基、羧基、-NRaRb、-C(O)NRaRb、-N(Ra)C(O)-(C1-20烷基)、-N(Ra)SO2-(C1-20烷基)、-SO2N(RaRb)、-C(O)O-(C1-20烷基)、-CHO、-OC(O)-(C1-20烷基)、-SO2-(C1-20烷基)、-SO2-(C6-20芳基)、-CO-(C6-20芳基)；Ra、Rb各自独立地为氢、C1-20烷基、C3-20环烷基或C6-20芳基。
在另一优选例中，所述苯基为
Figure PCTCN2016073387-appb-000018
其中R1’、R2’、R3’、R4’、R5’各自独立地为氢、卤素、C1-20烷基、卤代C1-20烷基、卤代C1-20烷氧基、C1-20 烷氧基、C3-20环烷基、C3-20环烷氧基。
在另一优选例中，所述吡啶基为
Figure PCTCN2016073387-appb-000019
或
Figure PCTCN2016073387-appb-000020
其中R21、R31、R41、R51、R12、R32、R42、R52、R13、R23、R43、R53各自独立地为氢、卤素、C1-20烷基、卤代C1-20烷基、卤代C1-20烷氧基、C1-20烷氧基、C3-20环烷基、C3-20环烷氧基。
在另一优选例中，
Figure PCTCN2016073387-appb-000021
选自：
Figure PCTCN2016073387-appb-000022
或
Figure PCTCN2016073387-appb-000023
L1为一个键、或-(CRyRx)r1(O)r2(CRyRx)r3-；其中，Ry、Rx各自独立地为氢；r1、r3各自独立地为0、1、2或3；r2为0或1；
每个R0相同或不同，各自独立地为氢。
在另一优选例中，R1、R2、R3、R4各自独立地为氢、卤素、C1-20烷基、C3-20环烷基；
R5为氢；和/或
R6为C1-20烷基、-NRaRb；其中，Ra、Rb各自独立地为氢、或C1-20烷基。
在另一优选例中，r1为1、2或3；r2为1；r3为0。
在另一优选例中，r1为1；r2为1；r3为0。
在另一优选例中，R1、R3各自独立地为氢、卤素、C1-20烷基或C3-20环烷基；R2和R4为氢。
在另一优选例中，C1-20烷基为甲基、乙基、正丙基、异丙基、正丁基。
在另一优选例中，C3-20环烷基为环丙基。
在另一优选例中，卤代C1-20烷基为三氟甲基。
在另一优选例中，卤代C1-20烷氧基为三氟甲氧基、三氟乙氧基、二氟甲氧基。
在另一优选例中，C1-20烷氧基为甲氧基、乙氧基、异丙氧基、叔丁氧基、异丁氧基。
在另一优选例中，C3-20环烷氧基为环丙氧基。
在另一优选例中，卤素为氟或氯。
在另一优选例中，所述化合物选自下组：
Figure PCTCN2016073387-appb-000024
Figure PCTCN2016073387-appb-000025
在另一优选例中，所述化合物选自下组：
Figure PCTCN2016073387-appb-000026
在另一优选例中，所述的R1、R2、R3、R4、R5、R6、Ra、Rb、L1、Ry、Rx、W1、W2、n、m、R0、A等各自独立地为实施例中各具体式II化合物中相应的基团。
在另一优选例中，本发明的式II化合物为实施例部分中所注备的各具体化合物，尤其是Z-22至Z-168中任一化合物。
在另一优选例中，所述化合物为本申请实施例所制备的化合物。
本发明第二方面提供了一种药物组合物，所述组合物包括本发明第一方面所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药；以及药学可接受的载体。
本发明第三方面提供了如本发明第一方面所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药，或本发明第二方面所述药物组合物在制备治疗疾病或病症的药物中的应用。
在另一优选例中，所述疾病或病症选自疼痛、抑郁症、心血管疾病、呼吸系统疾病、精神疾病或其组合。
在另一优选例中，所述疾病或病症选自与HIV相关的疼痛、HIV治疗诱导的神经病变、三叉神经痛、带状疱疹后神经痛、急性疼痛、热敏感、结节病、肠易 激综合征、克罗恩病、与多发性硬化(MS)有关的疼痛、肌萎缩性侧索硬化(ALS)、糖尿病性神经病变、周围神经病变、关节炎、类风湿性关节炎、骨关节炎、动脉粥样硬化、突发性张力障碍、肌无力综合征、肌强直、恶性高热、囊性纤维化、假性醛固酮增多症、横纹肌溶解症、甲状腺功能减退、双相抑郁症、焦虑症、精神分裂症、钠通道毒素相关病症、家族性红斑性肢痛症、原发性红斑性肢痛症，家族性直肠疼痛、癌症、癫痫、局部和全身强直性发作、不宁腿综合征、心律失常、纤维肌痛、在由中风或神经损伤导致的缺血性疾病状态下的神经保护、快速性心律失常、心房颤动和心室颤动。
在另一优选例中，所述疼痛选自神经性疼痛、炎性疼痛、内脏疼痛、癌症疼痛、化疗疼痛、创伤疼痛、手术疼痛、手术后疼痛、生产疼痛、分娩疼痛、牙痛、慢性疼痛、持续性疼痛、外周介导的疼痛、中枢介导的疼痛、慢性头痛、偏头痛、窦性头痛、紧张性头痛、幻肢痛、周围神经损伤、三叉神经痛、带状疱疹后神经痛、急性疼痛、家族性红斑性肢痛症、原发性红斑性肢痛症、家族性直肠疼痛或纤维肌痛或其组合。
本发明第四方面提供了一种治疗哺乳动物疾病或病症的方法，所述方法包括给需要的对象(如哺乳动物)施用治疗有效量的本发明第一方面所述的化合物，或其药学上可接受的盐、溶剂化物、立体异构体或前药，或本发明第二方面所述的药物组合物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1显示了化合物Z-40在脊神经结扎大鼠模型中大鼠冷痛觉测试基线。
图2显示了化合物Z-40在脊神经结扎大鼠模型中抑制冷刺激痛觉超敏效果。
图3显示了化合物Z-73在脊神经结扎大鼠模型中大鼠冷痛觉测试基线。
图4显示了化合物Z-73在脊神经结扎大鼠模型中抑制冷刺激痛觉超敏效果。
图5显示了化合物Z-22在脊神经结扎大鼠模型中大鼠冷痛觉测试基线。
图6显示了化合物Z-22在脊神经结扎大鼠模型中化合物抑制冷刺激痛觉超敏效果
图7显示了化合物Z-47和Z-54在脊神经结扎大鼠模型中大鼠冷痛觉测试基 线。
图8显示了化合物Z-47和Z-54在脊神经结扎大鼠模型中抑制冷刺激痛觉超敏效果。
具体实施方式
本发明人经过广泛而深入的研究，意外地发现了本发明的杂环取代的N-磺酰基苯甲酰胺衍生物对Nav1.7具有较高的抑制活性，同时对Nav1.5的抑制活性明显较弱，对Nav1.7具有明显的选择抑制活性。同时在疼痛模型测试中还显示出明显的镇痛效果，因此本发明的系列化合物可开发成用于广泛疼痛的治疗的药物。在此基础上，发明人完成了本发明。
术语定义
如本文所用，“C1-20烷基”指包含1至20个碳原子的直链和支链的饱和的脂族烃基，如下定义类似；更优选为C1-10烷基，非限制性的例子包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等；更优选为C1-6烷基，最优选为C1-3烷基。
如本文所用，“烯基”指至少由两个碳原子和至少一个碳-碳双键组成的如上定义的脂族烃基，“C2-20烯基”是指包含2至20个碳原子的直链和支链的烯基，如下定义类似；更优选为C2-10烯基；更优选为C2-6烯基；最优选C2-4烯基，例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。
如本文所用，“炔基”指至少由两个碳原子和至少一个碳-碳三键组成的如上所定义的脂族烃基，“C2-20炔基”指包含2至20个碳原子的直链和支链的炔基，如下定义类似；更优选为C2-10炔基；更优选为C2-6炔基；更优选为C2-4炔基；例 如乙炔基、1-丙炔基、2-丙炔基、1-、2-或3-丁炔基等。
如本文所用，“环烷基”指饱和或部分不饱和单环或多环环状烃基，“C3-20环烷基”是指包含3至20个碳原子的环烃基，如下定义类似；更优选为C3-10环烷基；更优选为C3-8环烷基；最优选为C3-6环烷基。单环环烷基的非限制性实施例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等，优选环丙基、环戊基、环己烯基。多环环烷基的非限制性实施例包括螺环、稠环和桥环的环烷基。
如本文所用，“杂环烷基”和“杂环基”可互换使用，指饱和或部分不饱和单环或多环环状烃基，优选为3元至20元的杂环烷基(是指杂环烷基包含3至20个环原子，且其中一个或多个环原子选自氮、氧或S(O)t(其中t是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳)；更优选为3元至10元的杂环烷基，其中1～3个环原子是杂原子；更优选为3元至6元的杂环烷基；更优选为5元至6元的杂环烷基。单环杂环基的非限制性实施例包括吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、四氢呋喃基等。多环杂环基的非限制性实施例包括螺环、稠环和桥环的杂环基。
如本文所用，“部分不饱和”是指含有一个或多个不饱和键但不具有完全共轭的π电子系统。
如本文所用，“C1-20烷氧基”指-O-(C1-20烷基)，其中烷基的定义如上所述。优选C1-10烷氧基，更优选C1-6烷氧基，最优选C1-3烷氧基。非限制性实施例包含甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、叔丁氧基、异丁氧基、戊氧基等。
如本文所用，“C3-20环烷氧基”指-O-(C3-20环烷基)，其中环烷基的定义如上所述。优选C3-10环烷氧基，优选C3-8环烷氧基，更优选C3-6环烷氧基。非限制性实施例包含环丙氧基、环丁氧基、环戊氧基、环己氧基等。
如本文所用，“C6-20芳基”指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，指含有6至20个碳原子的芳基；更优选为C6-12芳基，更优选苯基和萘基，最优选苯基。
如本文所用，“一个键”指由其连接的两个基团通过一个共价键连接。
如本文所用，“卤素”指氟、氯、溴或碘。
如本文所用，“卤代”指基团中一个或多个(如1、2、3、4或5个)氢被卤素所取代。
例如，“卤代C1-20烷基”指烷基被一个或多个(如1、2、3、4或5个)卤素取代，其中烷基的定义如上所述。优选为卤代C1-10烷基，更优选为卤代C1-6烷基， 最优选为卤代C1-3烷基。卤代C1-20烷基的例子包括(但不限于)一氯乙基、二氯甲基、1,2-二氯乙基、一溴乙基、一氟乙基、一氟甲基、二氟甲基、三氟甲基等。
又例如，“卤代C1-20烷氧基”指烷氧基被一个或多个(如1、2、3、4或5个)卤素取代，其中烷氧基的定义如上所述。优选为卤代C1-10烷氧基，更优选为卤代C1-6烷氧基，最优选为卤代C1-3烷氧基。包括(但不限于)三氟甲氧基、三氟乙氧基、一氟甲氧基、一氟乙氧基、二氟甲氧基、二氟乙氧基等。
又例如，“卤代C3-20环烷基”指环烷基被一个或多个(如1、2、3、4或5个)卤素取代，其中环烷基的定义如上所述。优选为卤代C3-10环烷基，更优选为卤代C3-8环烷基，最优选为卤代C3-6环烷基。包括(但不限于)三氟环丙基、一氟环丙基、一氟环己基、二氟环丙基、二氟环己基等。
如本文所用，“氘代C1-20烷基”指烷基被一个或多个(如1、2、3、4或5个)氘原子取代，其中烷基的定义如上所述。优选为氘代C1-10烷基，更优选为氘代C1-6烷基，最优选为氘代C1-3烷基。氘代C1-20烷基的例子包括(但不限于)单氘代甲基、单氘代乙基、二氘代甲基、二氘代乙基、三氘代甲基、三氘代乙基等。
如本文所用，“C1-20羟烷基”指被羟基取代的C1-20烷基，其中烷基的定义如上所述。优选为C1-10羟烷基，更优选为C1-6羟烷基，最优选为C1-3羟烷基。
如本文所用，“氨基”指-NH2，“氰基”指-CN，“硝基”指-NO2，“苄基”指-CH2-苯基，“氧代基”指＝O，“羧基”指-C(O)OH，“硫醇”指-SH，“亚环丙基”结构为：
Figure PCTCN2016073387-appb-000027
如本文所用，“羧酸酯基”指-C(O)O-(C1-20烷基)或(C3-20环烷基)，其中烷基、环烷基的定义如上所述。
如本文所用，“C1-20烷硫基”指-S-(C1-20烷基)，其中烷基的定义如上所述。优选为C1-10烷硫基，更优选为C1-6烷硫基，最优选为C1-3烷硫基。
如本文所用，“C1-20烷基氨基”指-(C1-20烷基)-NH2或-NH2-(C1-20烷基)，其中烷基的定义如上所述。优选为C1-10烷基氨基，更优选为C1-6烷基氨基，最优选为C1-3烷基氨基。
如本文所用，“C3-20环烷硫基”指-S-(C3-20环烷基)，其中环烷基的定义如上所述。优选为C3-10环烷硫基，更优选为C3-8环烷硫基，最优选为C3-6环烷硫基。
如本文所用，“3元至20元的杂环烷基硫基”指-S-(3元至20元的杂环烷基)，其中杂环烷基的定义如上所述。优选为3元至10元的杂环烷基硫基。
如本文所用，“3元至20元的杂环烷基氧基”指-O-(3元至20元的杂环烷基)，其中杂环烷基的定义如上所述。优选为3元至10元的杂环烷基氧基。
如本文所用，“杂芳基环”与“杂芳基”可互换使用，是指具有5到10个环原子，优选5或6元单环杂芳基或8至10元双环杂芳基；环阵列中共享6、10或14个π电子；且除碳原子外还具有1到5个杂原子的基团。“杂原子”是指氮、氧或硫。
如本文所用，“3至7元单环”是指含3至7个环原子的饱和或部分不饱和的全碳单环。优选5至6元。单环的实例包括(但不限于)：环丙基环、环丁基环、环戊基环、环戊烯基环、环己基环、环己烯基环、环己二烯基环、环庚基环、环庚三烯基环、环辛基环等。
如本文所用，“3至7元单杂环”是指3至7元单环中的1、2或3个碳原子被选自氮、氧或硫的杂原子所取代。优选5至6元。单杂环的实例包括(但不限于)四氢呋喃环、四氢噻吩环、吡咯烷基环、哌啶环、吡咯啉环、噁唑烷环、哌嗪环、二氧戊环、吗啉环、硫代吗啉环、高哌嗪环、吡喃环等。
如本文所用，“8至10元双环”是指含8至10个环原子的饱和的全碳双环或部分不饱和的全碳双环，双环的实例包括(但不限于)：
Figure PCTCN2016073387-appb-000028
Figure PCTCN2016073387-appb-000029
如本文所用，“8至10元双杂环”是指8至10元双环中的1、2、3、4或5个碳原子被选自氮、氧或硫的杂原子所取代。双杂环的实例包括(但不限于)四氢喹啉环、四氢异喹啉环、十氢喹啉环等。
如本文所用，“5至6元单环杂芳基环”是指含5至6个环原子的单杂芳基环，例如包括(但不限于)：噻吩环、N-烷基吡咯环、呋喃环、噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、四唑环、异噁唑环、噁二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环等。
如本文所用，“8至10元双环杂芳基环”是指含8至10个环原子的双杂芳基环，例如包括(但不限于)：苯并呋喃环、苯并噻吩环、吲哚环、异吲哚环、喹啉环、异喹啉环、吲唑环、苯并噻唑环、苯并咪唑环、喹唑啉环、喹喔啉环、噌啉环、酞嗪环。
如本文所用，“苯并3至7元单环或苯并3至7元单杂环”是指含3至7个环原子的单环或单杂环稠合于苯环上形成的双环结构，优选苯并5至6元单环或苯并5至6元单杂环。非限制性实施例包含：
Figure PCTCN2016073387-appb-000030
Figure PCTCN2016073387-appb-000031
如本文所用，“5至6元单环杂芳基环并3至7元单环或5至6元单环杂芳基环并3至7元单杂环”是指3至7元单环或3至7元单杂环稠合于5至6元单环杂芳基环上形成的双环结构，非限制性实施例包含：
Figure PCTCN2016073387-appb-000032
Figure PCTCN2016073387-appb-000033
如本文所用，“取代的”指基团中的一个或多个氢原子，优选为1～5个氢原子彼此独立地被相应数目的取代基取代，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
如本文所用，烷基可以是取代的或未取代的，烯基可以是取代的或非取代的，炔基可以是取代的或非取代的，环烷基可以是取代的或未取代的，杂环基可以是取代的或未取代的，烷氧基可以是任选取代的或未取代的，环烷氧基可以是任选 取代的或未取代的，芳基可以是取代的或未取代的，3至7元单环可以是取代的或未取代的，3至7元单杂环可以是取代的或未取代的，8至10元双环可以是取代的或未取代的，8至10元双杂环可以是取代的或未取代的，苯并3至7元单环或苯并3至7元单杂环可以是取代的或未取代的，5至6元单环杂芳基环并3至7元单环或5至6元单环杂芳基环并3至7元单杂环可以是取代的或未取代的，上述基团为取代时，取代基优选为1至5个以下基团，独立地选自C1-20烷基、卤代C1-20烷基、C2-20烯基、C2-20炔基、C1-20烷氧基、C1-20烷硫基、C1-20烷基氨基、卤素、硫醇、羟基、硝基、氰基、C3-20环烷基、3元至20元的杂环基、C6-20芳基、5或6元单环杂芳基或8至10元双环杂芳基、C3-20环烷氧基、3元至20元的杂环烷基氧基、C3-20环烷硫基、3元至20元的杂环烷基硫基、氧代基、氨基、C1-20羟烷基、羧基或羧酸酯基。
制备方法
本发明提供了式(II)化合物的制备方法，本发明中的化合物可以通过多种合成操作容易地制备，这些操作是所属领域技术人员熟练掌握的。这些化合物的示例性制备方法可以包括(但不限于)下文所述的流程。
本发明式(II)化合物可以参照下述合成路线进行制备，在具体操作过程中，可以根据需要对方法中的步骤进行扩展或合并。
路线1
Figure PCTCN2016073387-appb-000034
步骤1：可先通过例如草酰氯、羰基二咪唑(CDI)、丙基膦酸酐、基于脲的酰胺偶联剂或碳二亚胺等试剂激活式(I-a)化合物中的羧基，随后在亲和性碱，例如4-二甲氨基吡啶、N,N-二甲基氨基丙基-N’-乙基碳二亚胺、4-二甲氨基吡啶/N,N- 二异丙基乙胺的存在下与式(I-b)化合物中的磺酰胺基团发生置换反应，生成式(I-c)化合物。
步骤2：式(I-c)化合物与式(I-d)化合物在碱体系的存在下，通过取代反应(例如亲和取代反应等)或偶联反应(如Suzuki偶联等)生成式(I-e)化合物，合适的碱体系包括存在于DMSO的叔丁醇钾、存在于DMF中的氢化钠、存在于DMF的碳酸钾等。
步骤3：式(I-e)化合物可与式(I-f)化合物发生取代反应生成式(II)化合物，式(I-f)中的Lev为离去基团，包括(但不限于)三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等。
路线2
Figure PCTCN2016073387-appb-000035
式(I-d)化合物可先与式(I-f)化合物发生取代反应生成式(I-g)化合物，随后与式(I-c)化合物反应生成式(II)化合物，反应条件分别同路线1中的步骤3和步骤2。
以上各步骤中的反应均是本领域技术人员已知的常规反应。如无特殊说明，合成路线中所使用的试剂和原料化合物均可市购得到，或本领域技术人员根据所设计的不同化合物结构参考已知方法制备得到。
与现有技术相比，本发明的主要优点在于：
提供了一系列结构新颖的杂环取代的N-磺酰基苯甲酰胺衍生物，其对Nav1.7具有高选择抑制活性，可用作广泛疼痛治疗的药物。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。除非另行定义，本文所用的术语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或同等的方法及材料皆可应用于本发明中。
如本文所用，DMF为二甲基甲酰胺，DMSO为二甲基亚砜，THF为四氢呋喃，DIEA为N,N-二异丙基乙胺，EA为乙酸乙酯，PE为石油醚，BINAP为(2R,3S)-2,2’-双二苯膦基-1,1’-联萘。如本文所用，室温是指约为25℃。
化合物1-a的制备方法：
Figure PCTCN2016073387-appb-000036
步骤a：将化合物1-a-1(14.8g，0.10mol)加入到三氟甲磺酸(150ml)中，混合物冷却到0℃，分批加入N-碘代丁二酰亚胺(24.75g，0.110mol)。混合物在室温下，搅拌2h。将反应液慢慢倒入冰水中，搅拌约15分钟。用石油醚(3x 100ml)萃取。有机相用硫代亚硫酸钠水溶液(100ml)洗涤，硫酸钠干燥。过滤旋干滤液，粗品用柱层析纯化，石油醚洗脱，得到化合物1-a-2(14.0g，产率：55％)为粉红色液体。1H NMR(400MHz,CDCl3)：δ:7.78(dd,J＝8.0，6.4Hz,1H)，6.94(dd,J＝8.8,7.2Hz,1H)。
步骤b：在N2保护下，将化合物1-a-2(14g，0.051mol)溶解在1,4-二氧六环(140ml)中，分别加入加三乙胺(15.6g，0.153mol)，水(10ml)，1,1’-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物(2.08g，2.55mmol)。混合物在10公斤的一氧化碳压力下，80℃搅拌18h。将反应液慢慢升温至室温，加入1N NaOH水溶液(250ml)，搅拌10分钟，用乙酸乙酯(250ml)萃取。水相用1N HCl水溶液调pH至2。用乙酸乙酯(3x 100ml)萃取,有机相用饱和食盐水(100ml)洗涤，有机相用硫酸钠干燥。过滤旋干滤液，得到化合物1-a-3(7.8g，产率：80％)为白色固体。MS m/z(ESI):193[M+H]+。纯度＝98％(UV214)。
步骤c：在N2保护下，将化合物1-a-3(7.8g，0.041mol)溶解在无水二氯甲烷(100ml)中，加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(11.65g，0.061mol)，DMAP(11.07g，0.090mol)。混合物在室温搅拌10分钟，加入甲基磺酰胺2(4.82g，0.061mol)。混合物在室温搅拌18h。向反应液中加150ml水中,混合物在室温搅拌0.5h，分出水相。水相用1N HCl水溶液调pH至3后，用二氯甲烷(3x 100ml)萃取,有机相用饱和食盐水(200ml)洗，硫酸钠干燥，40℃旋干。粗品过柱(100-200目硅胶),石油醚：乙酸乙酯＝(1:1)洗脱，得到化合物1-a(3.8g，产率：35％)为白色固体。MS m/z(ESI):270[M+H]+。纯度＝100％(UV214)。 1H NMR(400MHz,CDCl3)：δ:12.41(s,1H)，8.00(t,J＝7.6Hz,1H)，7.74(t,J＝10.0Hz,1H)，3.37(s,3H)。
化合物9-a的制备方法：
Figure PCTCN2016073387-appb-000037
步骤：向9-a-1(400mg，2.27mmol)的10ml 1,2-二氯乙烷溶液中加入甲基磺酰胺(268mg，2.73mmol)，HATU(2-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯)(1.3g，3.41mmol)，DIPEA(N，N-二异丙基乙胺)(880mg，6.81mmol)，DMAP(4-二甲氨基吡啶)(50mg)，60℃搅拌1h。反应结束，冷却至室温，加入二氯甲烷，3N盐酸洗，饱和碳酸氢钠洗，无水硫酸钠干燥，过滤，滤液减压浓缩得粗品，经Combi-flash柱层析纯化得到红色固体化合物9-a(250mg)，直接用于下一步反应，纯度45％，产率44％。MS m/z(ESI):252.0[M-H]+。
化合物11-a的制备方法：
Figure PCTCN2016073387-appb-000038
步骤a：化合物11-a-1(5g，31.6mmol)溶解于20ml硫酸中，冷却至0℃，加入1,3-二溴-5,5-二甲基海因(4.4g，15.5mmol)，0℃搅拌2h。反应结束，倒入冰水中，过滤得白色固体化合物11-a-2(6.62g)，纯度94.37％，产率88.62％，MS m/z(ESI):237[M+H]+。
步骤b：向11-a-2(3g，12.7mmol)，甲基磺酰胺(2.4g，25.4mmol)的300ml二氯甲烷溶液中加入HATU(2-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯)(7.2g，19.1mmol)，DIPEA(N，N-二异丙基乙胺)(3.3g，25.4mmol)，DMAP(4-二甲氨基吡啶)(159mg,1.3mmol)，室温搅拌过夜。反应结束，加入水洗，分离有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得粗品，经Combi-flash柱层析纯化得到红色固体化合物11-a(3.6g)，直接用于下一步反应，纯度88.2％，产率90％，MS m/z(ESI):314[M+H]+。
化合物13-a的制备方法：
Figure PCTCN2016073387-appb-000039
步骤a：将化合物13-a-1(50g,0.40mol)加入到浓盐酸(400ml)中，混合物冷却到0℃，滴加亚硝酸钠(28.6g,0.44mol)的水(100ml)溶液。混合物在0℃反应0.5h后，加入氯化亚铜(91.68g,0.48mol)。混合物在室温搅拌0.5h后，加热到100℃搅拌1h。冷却后过滤，滤液用石油醚(500ml x 2)萃取，有机相用饱和食盐水洗涤(500ml)，无水硫酸钠干燥，过滤，滤液减压蒸干，所得粗品通过柱层析提纯(eluent/PE:EA＝10:1)，得到到无色油状化合物13-a-2(24.1g，产率：41％)。1H NMR(400MHz,DMSO-d6)δ:14.10(brs,1H),12.50(brs,1H),7.87(d,J＝6.0Hz，1H),7.76(d,J＝10.0Hz，1H),3.38(s,3H)。
步骤b：将化合物13-a-2(18.72g,130mmol)溶解在无水THF(200ml)中，冷却至-78℃,氮气保护下，滴加n-BuLi(62.4ml,2.4M/L,248mmol)。混合物在-78℃搅拌1h，然后倒到干冰上。混合物在-78℃搅拌1h，然后在室温下搅拌1h。混合物倒入2N盐酸水溶液(200ml)中，用乙酸乙酯(250ml)萃取。分出有机相用食盐水(200ml)洗涤。无水硫酸钠干燥，过滤。滤液用旋转蒸发仪旋干滤液得白色固体13-a-3(9.1g，产率:37％).ESI-MS(M-H)-:187。纯度＝80％(UV214)。
步骤c：将化合物13-a-3(9.1g,48mmol)溶解在无水DCM(150mL)中，冷却至0℃，分别加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(13.76g,72mmol)，DMAP(11.8g,96mmol),甲基磺酰胺(9.12g,96mmol)。混合物在室温搅拌18h后，倒入2N盐酸水溶液(100ml)中，混合物在室温搅拌0.5h后，分出有机相用食盐水(100ml)洗涤。无水硫酸钠干燥，过滤。滤液用旋转蒸发仪旋干滤液得白色固体13-a-4(9.6g，产率:78％).ESI-MS(M+H)+:266.0。纯度＝91％(UV214)。
步骤d：将化合物13-a-4(7.95g,30mmol)溶解在无水DME(100ml)中，加 入NBS(12.21g,69mmol)，偶氮二异丁氰(0.59g,3mmol)。混合物在搅拌条件下，回流18h后，用旋转蒸发仪旋干滤液。残留物用HPLC柱制备得白色固体13-a-5(3.1g，产率:30％)。ESI-MS(M+H)+:343.7。纯度＝98.2％(UV214)。1H NMR(400MHz,CDCl3)δ:8.80(s,1H),8.12(d,J＝6.8Hz，1H),7.36(d,J＝12.0Hz，1H),4.54(s,2H),3.43(s,3H)。
步骤e：将化合物13-a-5(0.686mg,2mmol)加入到2％稀硫酸(25ml)中，搅拌下，加入高碘酸钠(856mg,4mmol)。混合物在100℃反应18h。用乙酸乙酯(3x 50ml)萃取，有机相用10％硫代硫酸钠洗涤(50ml)。无水硫酸钠干燥，过滤，滤液减压蒸干，所得粗品通过柱层析提纯(DCM:MeOH＝10:1)，得到白色固体13-a(266mg，产率：41.6％)。ESI-MS(M+H)+:295.8。纯度＝98.5％(UV214)。1H NMR(400MHz,DMSO-d6)δ:14.10(brs,1H),12.50(brs,1H),7.87(d,J＝6.0Hz，1H),7.76(d,J＝10.0Hz，1H),3.38(s,3H)。
化合物15-a的制备方法：
Figure PCTCN2016073387-appb-000040
步骤：将化合物15-a-1(500mg,2.4mmol)溶解在2-甲基丙-1-醇(2.7g，36mmol)中，加入碳酸铯(1.6g,4.8mmol)。180℃搅拌30分钟。反应结束，冷却至室温，倒入水中，用乙酸乙酯(2x 50ml)萃取，无水硫酸钠干燥，过滤，滤液减压浓缩得到无色油状化合物15-a(400mg，产率：63.5％)。
化合物17-a的制备方法：
Figure PCTCN2016073387-appb-000041
步骤a：向化合物17-a-1(4.5g,28.8mmol)，对甲苯磺酸(499mg,2.9mmol)的二氯甲烷(100ml)溶液中，冷却至零摄氏度缓慢加入N-氯代丁二酰亚胺(4g,30.3mmol)，搅拌2小时，室温搅拌过夜。反应结束，倒入水中，用乙酸乙酯萃取，无水硫酸钠干燥，过滤，滤液减压浓缩得到白色固体化合物17-a-2(5g)。MSm/z(ESI):189[M-1]-。
步骤b：向化合物17-a-2(5g,26.3mmol)的甲醇(130ml)溶液中逐滴加入浓硫 酸(7ml,1mmol)，回流搅拌5小时。反应结束，冷却至室温，倒入水中，用乙酸乙酯萃取，无水硫酸钠干燥，过滤，滤液减压浓缩，加入二氯甲烷室温搅拌20分钟，过滤得到白色固体化合物17-a(4.2g)。MS m/z(ESI):203[M-1]-。
化合物22-a的制备方法：
Figure PCTCN2016073387-appb-000042
步骤a：以化合物17-a(2g)为原料参照实施例57中步骤3的制备方法，不同的是将反应条件换成室温搅拌过夜，得到化合物22-a-2(552mg)，纯度96.57％，产率14％，MS m/z(ESI):322.1[M+H-56]+。
步骤b：向50ml单口圆底烧瓶中加入化合物22-a-2(552mg)，盐酸(4M，5ml，20mmol)，甲醇5ml，室温搅拌过夜。反应结束，反应液减压浓缩得到固体化合物22-a(409mg)，纯度100％，产率41％，MS m/z(ESI):288[M+H]+，直接用于下一步反应。
化合物23-a的制备方法：
Figure PCTCN2016073387-appb-000043
步骤a：以化合物23-a-1(1g)为原料参照实施例29中步骤2的制备方法，得到化合物23-a-2(683mg)，纯度83.85％，产率83％，MS m/z(ESI):168.1[M+H]+。
步骤b：向化合物23-a-2(385mg，2.296mmol)的乙腈(5ml)溶液中零摄氏度加入对甲基苯磺酸(474mg，2.756mmol)，4-氯苯胺与叔丁基亚硝酸酯(284mg，2.756mmol)，四丁基溴化铵(1479mg，4.593mmol)，溴化亚铜(33mg，0.23mmol)，室温搅拌1小时。反应结束，食盐水洗，干燥分离有机相，减压浓缩得粗品，经Combi-flash柱层析纯化得到无色油状化合物23-a(394mg)，纯度73.57％，产率75％。
化合物24-a的制备方法：
化合物24-a以化合物4-溴苯胺为起始原料，参照化合物23-a的方法进行制备。
化合物25-a的制备方法：
Figure PCTCN2016073387-appb-000045
步骤：向化合物25-a-1(2.03g，11.93mmol)的乙酸(65ml)溶液中加入溴(0.61ml，11.33mmol)，室温搅拌过夜。反应结束，减压浓缩，食盐水洗，乙酸乙酯萃取，干燥分离有机相，减压浓缩得粗品，经Combi-flash柱层析纯化得到化合物25-a(3g)，纯度85％，产率100％。MS m/z(ESI):249[M+H]+。
实施例22：(R)-5-氯-4-((1-(3-氯-4-(三氟甲氧基)苯基)吡咯烷-2-基)甲氧基)-2-氟-N-(甲基磺酰基)苯甲酰胺(Z-22)的制备
Figure PCTCN2016073387-appb-000046
步骤1：向50ml密封管中加入4-溴-2-氯-1-(三氟甲氧基)苯(215mg，0.781mmol)，化合物7-a(117mg)，Pd2(dba)3(三(二亚苄基丙酮)二钯)(36mg，0.039mmol)，BINAP((±)-2,2’-双-(二苯膦基)-1,1’-联萘)(51mg，0.082mmol)，叔丁基醇钾(263mg，2.344mmol)，7ml 1,4-二氧六环，90℃搅拌2h。反应结束，冷却至室温，加入30ml水和30ml乙酸乙酯，过滤，乙酸乙酯萃取，分离合并有机相，滤液减压浓缩得到粗品，经Combi-flash柱层析纯化得到黄色油状化合物22-b(51.5mg)，直接用于下一步反应，纯度53％，产率41％，MS m/z(ESI):296[M+H]+。
步骤2：化合物22-b(148.6mg)，5-氯-2,4-二氟-N-(甲基磺酰基)苯甲酰胺(107mg，0.397mmol)，碳酸铯(260mg，0.798mmol)，6ml二甲基亚砜的混合物，在微波条件下，220℃搅拌30分钟。反应结束，冷却至室温，加入30ml水，调pH 为6～7，乙酸乙酯萃取，分离有机相，减压浓缩得到深度油状物300mg，经Combi-flash柱层析纯化得到白色固体化合物Z-22(69mg)，纯度79％，产率16.3％，MS m/z(ESI):545[M+H]+。1H NMR(500MHz,DMSO-d6)δ12.14(s,1H),7.78(d,J＝7.5Hz,1H),7.31(d,J＝9.0Hz,1H),7.19(d,J＝12.1Hz,1H),6.91(d,J＝2.5Hz,1H),6.71(dd,J＝9.5,2.9Hz,1H),4.25(s,1H),4.16(m,2H),3.48(t,J＝8.6Hz,1H),3.24(s,3H),3.15(d,J＝6.5Hz,1H),2.23(d,J＝7.5Hz,1H),2.12–1.92(m,3H).
实施例23-25：
化合物Z-23以化合物7-a为起始原料，参照实施例22的方法进行制备，不同的是将步骤1中4-溴-2-氯-1-(三氟甲氧基)苯换成4-溴-1,2-二氯苯。
化合物Z-28参照实施例22的方法进行制备，不同的是将步骤1中化合物7-a换成(S)-吡咯烷-2-基甲醇。
化合物Z-29参照实施例22的方法进行制备，不同的是将步骤1中化合物7-a换成(S)-吡咯烷-2-基甲醇，4-溴-2-氯-1-(三氟甲氧基)苯换成4-溴-1,2-二氯苯。
Figure PCTCN2016073387-appb-000047
实施例33：(R)-5-氯-4-(1-(3-氯-4-(三氟甲氧基)苯基)吡咯烷-3-基氧基)-2-氟 -N-(甲基磺酰基)苯甲酰胺(Z-33)的制备
Figure PCTCN2016073387-appb-000048
步骤1：向50ml单口圆底烧瓶中加入化合物14-a(644mg)，盐酸(4M，5ml，20mmol)，甲醇5ml，室温搅拌过夜。反应结束，反应液减压浓缩得到黄色固体化合物33-b(425mg)，直接用于下一步反应，产率100％。
步骤2：以化合物33-b(425mg)为原料参照实施例22中步骤1的制备方法，得到黄色油状化合物33-c(520mg)，纯度83.4％，产率80.7％，MSm/z(ESI):282[M+H]+。
步骤3：向单口圆底烧瓶中加入化合物33-c(288mg，1.0225mmol)，叔丁醇钾(344mg，3.065mmol)，THF10ml，冰浴搅拌2分钟，加入化合物1-a(358mg，1.327mmol)，搅拌30分钟。反应结束，加入水(10ml x 3)和乙酸乙酯萃取(10ml x3)，分离合并有机相，减压浓缩得到粗品，经液相制备纯化得到固体化合物Z-33(4.6mg)，纯度100％，产率0.7％。MS m/z(ESI):531[M+H]+。1H NMR(500MHz,DMSO-d6)δ7.765(d,J＝8Hz,1H),7.315(d,J＝8Hz,1H),7.110(d,J＝12Hz,1H),6.765(d,J＝3Hz,1H),6.583-6.607(m,1H),5.312(s,1H),3.701(dd,J＝11.5,4.5Hz,1H),3.446-3.410(m,3H),3.328(s,2H),2.818(s,3H).
实施例38-49：
化合物Z-38至Z-41、Z-43、Z-44、Z-46、Z-47、Z-49可参照本发明实施例22-33的类似方法制备。
Figure PCTCN2016073387-appb-000049
实施例50：(R)-5-氯-2-氟-N-(甲基磺酰基)-4-((1-(4-(三氟甲氧基)苯基)吡咯烷-2-基)甲氧基)苯甲酰胺(Z-50)的制备
Figure PCTCN2016073387-appb-000050
步骤1：1-溴-4-(三氟甲氧基)苯(1g，4.15mmol)，化合物7-a(0.63g，6.22mmol),(S)-脯氨酸(96mg，0.83mmol)，碘化亚铜(79mg，0.415mmol)，碳酸钾(1.72g，12.45mmol)的二甲基亚砜(10ml)混合溶液，氮气保护90℃搅拌4h。反应结束，冷却至室温，倒入水和乙酸乙酯萃取，食盐水洗，干燥分离有机相，滤液减压浓缩得到粗品，经Combi-flash柱层析纯化得到黄色油状化合物50-b(186mg)，直接用于下一步反应，纯度82％，产率17％。MS m/z(ESI):262.1[M+H]+。
步骤2：以化合物50-b(119mg)为原料，参照实施例22中步骤2的制备方法，得到白色固体化合物Z-50(52.17mg)，纯度100％，MS m/z(ESI):509[M-H]-。1H NMR(500MHz,DMSO-d6):δ12.11(s,1H),7.78(d,J＝7.5Hz,1H),7.16(m,3H),6.74(d,9.0Hz,2H)，4.18(d,J＝7.0Hz,2H),4.13-4.08(m,1H),3.46(t,J＝6.8Hz,1H),3.20(s,3H),3.17-3.11(m,1H),2.27-2.21(m,1H),2.10-2.04(m,2H),2.05-2.00(m,1H).
实施例51-52、56、58-59、67-69、71-72、76、79
化合物Z-51以化合物7-a为起始原料，参照实施例50的方法进行制备，不同的是将步骤1中1-溴-4-(三氟甲氧基)苯换成1-溴-2,4-二氯苯，反应条件换成140℃搅拌30分钟。
化合物Z-52以化合物7-a为起始原料，参照实施例50的方法进行制备，不同的是将步骤1中1-溴-4-(三氟甲氧基)苯换成4-溴-2-氯-1-氟苯，反应条件换成90℃搅拌过夜。
化合物Z-56以化合物7-a为起始原料，参照实施例50的方法进行制备，不同的是将步骤1中1-溴-4-(三氟甲氧基)苯换成4-溴-2-氯苯甲腈，反应条件换成140℃搅拌30分钟。
化合物Z-58以化合物7-a为起始原料，参照实施例50的方法进行制备，不同的是将步骤1中1-溴-4-(三氟甲氧基)苯换成2-溴-5-氯吡啶，反应条件换成110℃搅拌5小时。
化合物Z-59以化合物7-a为起始原料，参照实施例50的方法进行制备，不同的是将步骤1中1-溴-4-(三氟甲氧基)苯换成3-溴-5-氯吡啶，反应条件换成110℃搅拌过夜。
化合物Z-67以化合物7-a为起始原料，参照实施例50的方法进行制备，不同的是将步骤1中1-溴-4-(三氟甲氧基)苯换成1-溴-4-(三氟甲基)苯，反应条件换成100℃搅拌20小时。
化合物Z-68以化合物7-a为起始原料，参照实施例50的方法进行制备，不同的是将步骤1中1-溴-4-(三氟甲氧基)苯换成4-溴-1-氯-2-氟苯，反应条件换成90℃搅拌8小时。
化合物Z-69以化合物7-a为起始原料，参照实施例50的方法进行制备，不同的是将步骤1中1-溴-4-(三氟甲氧基)苯换成4-溴-2-氟-1-(三氟甲基)苯，反应条件换成110℃搅拌过夜。
化合物Z-71以化合物7-a为起始原料，参照实施例50的方法进行制备，不同的是将步骤1中1-溴-4-(三氟甲氧基)苯换成5-溴-2-(三氟甲基)吡啶，反应条件换成100℃搅拌过夜，步骤2反应条件换成180℃搅拌30分钟。
化合物Z-72以化合物7-a为起始原料，参照实施例50的方法进行制备，不同的是将步骤1中1-溴-4-(三氟甲氧基)苯换成1-溴-4-(三氟甲基)苯，反应条件换成100℃搅拌20小时，步骤2中化合物1-a换成化合物9-a，反应条件换成200℃搅拌30分钟。
化合物Z-76，Z-79以化合物7-a为起始原料，参照实施例50的方法进行制备，不同的是将步骤1中1-溴-4-(三氟甲氧基)苯分别换成化合物23-a，24-a，反应条件换成140℃搅拌30分钟，步骤2中反应条件换成200℃搅拌30分钟。
Figure PCTCN2016073387-appb-000051
Figure PCTCN2016073387-appb-000052
Figure PCTCN2016073387-appb-000053
实施例53：(R)-5-氯-4-(((1-(3-氯-4-(三氟甲氧基)苯基)吡咯烷-2-基)甲基)硫基)-2-氟-N-(甲磺酰基)苯甲酰胺(Z-53)的制备
Figure PCTCN2016073387-appb-000054
步骤1：化合物22-b(504mg，1.704mmol)，对甲苯磺酰氯(415mg，2.045mmol)，三乙胺(350mg，3.239mmol)，4-二甲氨基吡啶(25mg，0.17mmol)的10ml二氯甲烷混合溶液，室温搅拌6小时。反应结束，加入1M盐酸溶液和碳酸氢钠溶液洗，干燥分离有机相，减压浓缩得粗品化合物53-b(754mg)。MS m/z(ESI):450.1[M+H]+。
步骤2：化合物53-b(424mg，0.942mmol)的二甲基甲酰胺(5ml)溶液中加入硫代乙酰钾(548mg，4.807mmol)，140℃搅拌1小时。反应结束，冷却至室温，加入水和乙酸乙酯萃取，干燥分离有机相，减压浓缩得粗品，经Combi-flash柱层 析纯化得到黄色油状化合物53-c(156mg)，纯度100％，产率49％。MS m/z(ESI):354.1[M+H]+。
步骤3：以化合物53-c(150mg)为原料，参照实施例22中步骤2的制备方法，得到白色固体化合物Z-53(144mg)，纯度96.65％，产率38％，MS m/z(ESI):561[M+H]+。1H NMR(DMSO-d6,400MHz):＝7.74(d,J＝7.2Hz,1H),7.25-7.35(m,2H),6.69(d,J＝2.8Hz,1H),6.57(dd,J＝9.2,2.8Hz,1H),4.04(br.s.,1H),3.39-3.49(m,1H),3.08-3.28(m,3H),2.96(s,3H),2.10-2.22(m,1H),1.90-2.10ppm(m,3H)。
实施例54:(R)-4-((1-(3-氯-4-(三氟甲氧基)苯基)吡咯烷-2-基)甲氧基)-5-环丙基-2-氟-N-(甲磺酰基)苯甲酰胺(Z-54)的制备
Figure PCTCN2016073387-appb-000055
步骤1：以化合物22-b(200mg)为原料，参照实施例22中步骤2的制备方法，不同的是将化合物1-a换成化合物11-a，得到白色固体化合物54-b(110mg)，纯度72％，产率18.39％，MS m/z(ESI):589[M+H]+。
步骤2：化合物54-b(100mg，0.17mmol)，环丙基硼酸(29.13mg，0.34mmol),碳酸钾(46.87mg，0.34mmol)，醋酸钯(7.613mg，0.034mmol)加入甲苯(20ml)和水(2ml)中，加入三环己基膦(47.55mg，0.17mmol)，氮气保护100℃搅拌过夜。反应结束，冷却至室温，水洗，食盐水洗，分离有机相，减压浓缩得到粗品，经Combi-flash柱层析纯化得到化合物Z-54(32mg)。MS m/z(ESI):551[M+H]+。1H NMR(DMSO-d6,500MHz):＝11.92(br.s.,1H),7.30(d,J＝8.0Hz,1H),7.14(d,J＝8.0Hz,1H),6.84-6.95(m,2H),6.72(dd,J＝9.5,3.0Hz,1H),4.30(d,J＝5.5Hz,1H),4.07(d,J＝5.5Hz,2H),3.50(t,J＝8.0Hz,1H),3.10-3.25(m,4H),2.12-2.25(m,1H),1.90-2.11(m,4H),0.83-0.94(m,1H),0.54-0.76ppm(m,3H)
实施例55：(R)-4-((1-(3-氯-4-(三氟甲氧基)苯基)吡咯烷-2-基)甲氧基)-3-氰基-N-(甲磺酰基)苯甲酰胺(Z-55)的制备
Figure PCTCN2016073387-appb-000056
步骤1：化合物16-a(3g，13.7mmol)，甲磺酰胺(1.95g，20.5mmol),2-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)(5.73g，15.07mmol)，三乙胺(2.77mg，27.4mmol)的二氯甲烷(30ml)混合溶液，室温搅拌16小时。反应结束，2N盐酸溶液洗，水洗，食盐水洗，干燥分离有机相，减压浓缩得到粗品，经Combi-flash柱层析纯化得到化合物，加入乙酸乙酯和石油醚，过滤，石油醚洗，得白色固体化合物55-b(1.5g)。MS m/z(ESI):295.9[M+H]+。
步骤2：化合物55-b(1g，3.38mmol)，氰化锌(237mg，2.03mmol),三(二亚苄基丙酮)二钯(31mg，0.034mmol)，1,1’-双(二苯基膦)二茂铁(38mg，0.068mmol)，锌(9mg，0.135mmol)，醋酸锌(25mg，0.135mmol)的二氧六环(15ml)混合溶液，110℃搅拌5小时。反应结束，冷却至室温，过滤，乙酸乙酯洗，减压浓缩，加入乙酸乙酯和石油醚，过滤，石油醚洗，干燥，经Combi-flash柱层析纯化得到化合物得黄色固体化合物55-c(238mg)。MS m/z(ESI):241[M-H]-。
步骤3：以化合物22-b(100mg)为原料，参照实施例22中步骤2的制备方法，不同的是将化合物1-a换成化合物55-c，得到黄色固体化合物Z-55(44mg)，MS m/z(ESI):518[M+H]+。1H NMR(DMSO-d6,500MHz):＝8.21(d,J＝2.5Hz,1H),8.16(dd,J＝9.0,2.0Hz,1H),7.29(dd,J＝9.0,2.0Hz,2H),6.83(d,J＝3.0Hz,1H),6.75(dd,J＝9.5,2.5Hz,1H),4.25(d,J＝7.0Hz,2H),4.11-4.23(m,1H),3.49(t,J＝8.5Hz,1H),3.12-3.21(m,1H),3.08(s,3H),2.22-2.35(m,1H),2.05-2.15(m,2H),2.01ppm(br.s.,1H)
实施例57：(R)-5-氯-4-(1-(1-(3-氯-4-(三氟甲氧基)苯基)吡咯烷-2-基)乙氧基)-2-氟-N-(甲磺酰基)苯甲酰胺(Z-57)的制备
Figure PCTCN2016073387-appb-000057
步骤1：向化合物22-b(600mg，2.029mmol)的二氯甲烷(20ml)溶液中0℃加入戴斯-马丁氧化剂(1.033g，2.435mmol)，0℃搅拌30分钟。反应结束，加入碳酸氢钠溶液，硫代硫酸钠溶液，二氯甲烷萃取，碳酸氢钠溶液洗，干燥分离有机相，减压浓缩得到粗品黄色油状化合物57-b(575mg)。MS m/z(ESI):294[M+H]+。
步骤2：向化合物57-b(0.575g，1.958mmol)的四氢呋喃(5ml)溶液中0℃逐滴加入甲基溴化镁(1ml，2.937mmol)，自然升至室温搅拌1小时。反应结束，加入氯化铵溶液，乙酸乙酯萃取，食盐水洗，干燥分离有机相，减压浓缩得到粗品黄色油状化合物57-c(339mg)。MS m/z(ESI):310.1[M+H]+。
步骤3：向化合物57-c(339mg，1.094mmol)，化合物17-a(224mg，1.094mmol)，三苯基膦(576mg，2.189mmol)的甲苯(5ml)溶液中氩气保护下加入偶氮二甲酸二异丙酯(443mg，2.189mmol)，氩气保护60℃搅拌过夜。反应结束，冷却至室温，倒入水中，乙酸乙酯萃取，食盐水洗，干燥分离有机相，减压浓缩。经Combi-flash柱层析纯化得到黄色油状化合物57-d(276mg)。MS m/z(ESI):496.1[M+H]+。
步骤4：向化合物57-d(276mg，0.556mmol)的甲醇(10ml)溶液中加入氢氧化钠(89mg，2.224mmol)的水(1ml)溶液，室温搅拌过夜。反应结束，减压浓缩，加入水，1N盐酸调节PH为1，乙酸乙酯萃取，食盐水洗，干燥分离有机相，减压浓缩得到化合物得黄色油状化合物57-e(266mg)。MS m/z(ESI):482[M+H]+。
步骤5：向50ml单口圆底烧瓶中加入3-氯-4-(三氟甲氧基)苯甲酸(31g，0.129mmol)，化合物57-e(87mg)，甲磺酰胺，HATU(2-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯)(99mg，0.260mmol)，DIPEA(N，N-二异丙基乙胺)(56mg，0.433mmol)，二甲基甲酰胺3ml，室温搅拌过夜。反应结束，加入20ml水，调节pH为4～5，乙酸乙酯萃取(20ml x 3)，分离有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得到油状物(120mg)，经制备液相分离纯化得黄色油状化合物Z-57 (19mg)。MS m/z(ESI):559[M+H]+。1H NMR(500MHz,DMSO-d6):δ12.06-12.02(br.s.,1H),7.75(d,J＝7.5Hz,1H),7.30(d,J＝9.0Hz,1H),7.07(d,J＝7.0Hz,1H),6.78(d,J＝2.5Hz,1H),6.64(dd,J＝2.5Hz,9.0Hz,1H),4.99-4.95(m,1H),4.01(d,J＝8.5Hz,1H),3.37-3.34(m,1H),3.16(s,3H),3.14-3.09(m,1H),2.37-2.31(m,1H),2.28-2.23(m,1H),2.06-1.99(m,1H),1.98-1.92(m,1H),1.32(d,J＝6.0Hz,3H).
实施例60：(R)-4-((1-(3-氯-4-(三氟甲基)苯基)吡咯烷-2-基)甲氧基)-2,5-二氟-N-(甲磺酰基)苯甲酰胺(Z-60)的制备
Figure PCTCN2016073387-appb-000058
步骤1：以化合物7-a(2.92g)为起始原料，参照实施例50的方法进行制备，不同的是将步骤1中1-溴-4-(三氟甲氧基)苯换成4-溴-2-氯-1-(三氟甲基)苯，反应条件换成100℃搅拌16小时。得到黄色油状化合物60-b(2.076g)，直接用于下一步反应，纯度91.7％，产率31％。MS m/z(ESI):280.1[M+H]+。
步骤2：向化合物60-b(55mg，0.197mmol)的四氢呋喃(10ml)溶液中0℃加入叔丁醇钾(66mg，0.592mmol)，0℃搅拌10分钟，加入化合物9-a(50mg，0.197mmol)，自然升至室温搅拌2小时。反应结束，乙酸乙酯萃取，盐酸溶液洗至PH为5-6，干燥分离有机相，经prep-HPLC纯化得到白色固体化合物Z-60(22mg)。MSm/z(ESI):511.1[M-H]-。1H NMR(500MHz,DMSO-6):δ12.08(s,1H),7.60-7.57(m,1H),7.53(d,J＝9.0Hz,1H),7.28-7.25(m,1H),6.92(d,J＝2.0Hz,1H),6.73(dd,J＝9.0Hz,4.0Hz,1H),4.34-4.33(m,1H),4.20-4.13(m,2H),3.52-3.49(m,1H),3.35(s,3H),3.24-3.21(m,1H),2.18-2.15(m,1H),2.11-2.05(m,3H).
实施例81：(R)-5-氯-N-(乙基磺酰基)-2-氟-4-((1-(4-(三氟甲基)苯基)吡咯烷-2-基)甲氧基)苯甲酰胺(Z-81)的制备
Figure PCTCN2016073387-appb-000059
步骤1：化合物7-a(6.08g)，1-溴-4-(三氟甲基)苯(9g，40mmol)，4,7-二甲氧基-1,10-菲咯啉(920mg，8mmol)，碘化亚铜(764mg，4mmol)，碳酸钾(16.56g，120mmol)的二甲基亚砜(20ml)混合溶液，氩气保护140℃微波搅拌30分钟。反应结束，冷却至室温，倒入水中，乙酸乙酯萃取，食盐水洗，干燥分离有机相，减压浓缩。经Combi-flash柱层析纯化得到黄色油状物81-b(3.98g)。
步骤2：以化合物81-b(956mg)为原料，参照实施例57中步骤3的制备方法，得到黄色油状化合物81-c(1.1g)，MS m/z(ESI):432.2[M+H]+。
步骤3：以化合物81-c(1.1g)为原料，参照实施例57中步骤4的制备方法，得到黄色油状化合物81-d(0.84g)，MS m/z(ESI):398.1[M+H]+。
步骤4：以化合物81-d(100mg)和乙烷磺酰胺(52mg)为原料，参照化合物11-a中步骤b的制备方法，得到白色固体化合物Z-81(50mg)，MS m/z(ESI):509.2[M+H]+。1H NMR(DMSO-d6,400MHz):＝7.72(d,J＝7.6Hz,1H),7.42(d,J＝8.8Hz,2H),6.96(d,J＝12.4Hz,1H),6.78(d,J＝8.8Hz,2H),4.23(br.s.,1H),4.02-4.15(m,2H),3.47(t,J＝8.8Hz,1H),3.12-3.23(m,1H),3.05(q,J＝7.2Hz,2H),2.13-2.31(m,1H),1.91-2.11(m,3H),1.08ppm(t,J＝7.2Hz,3H).
实施例121、122、126、127、135、137、141、152、153
化合物Z-121、Z-122、Z-126、Z-127、Z-135、Z-137、Z-141、Z-152、Z-153均以化合物7-a为起始原料，参照化合物Z-81的方法进行制备。不同的是根据各自结构，将步骤1中1-溴-4-氯苯换成分别换成5-溴-2-(三氟甲基)吡啶、溴苯、2-溴嘧啶、2-溴-5-氯嘧啶、4溴嘧啶、2-溴-5-(三氟甲基)吡啶，将步骤4中的乙烷磺酰胺或分别换成甲基磺酰胺或异丙烷磺酰胺。
Figure PCTCN2016073387-appb-000060
Figure PCTCN2016073387-appb-000061
实施例63：(R)-4-((1-(3-氯-4-氟苯基)吡咯烷-2-基)甲氧基)-5-环丙基-2-氟-N-(甲磺酰基)苯甲酰胺(Z-63)的制备
Figure PCTCN2016073387-appb-000062
步骤1：以化合物7-a(728mg)为起始原料，参照实施例50步骤1的方法制备，不同的是将1-溴-4-(三氟甲氧基)苯换成4-溴-2-氯-1-氟苯，反应条件换成90℃搅拌过夜，得到白色固体化合物63-b(120mg)，MS m/z(ESI):230[M+H]+。
步骤2：以化合物63-b(110mg)为起始原料，参照实施例22步骤2的方法进行制备，不同的是将步骤中化合物1-a换成化合物11-a，反应条件换成180℃搅拌1小时，得到白色固体化合物63-c(120mg)，MS m/z(ESI):523[M+H]+。
步骤3向化合物63-c(130.5mg)，环丙基硼酸(43mg，0.5mmol)的10ml二氧六环溶液中加入[1,1’-双(二苯基膦基)二茂铁]二氯化钯(22mg，0.03mmol)，碳酸铯(163mg，0.5mmol),氩气保护，100℃搅拌过夜。反应结束，冷却至室温，过滤，倒入水中，乙酸乙酯萃取，无水硫酸钠干燥有机相，减压浓缩得粗品，经制备液相分离纯化,得到白色固体化合物Z-63(12mg)，MS m/z(ESI):485[M+H]+。1H NMR(500MHz,DMSO-d6):δ11.907(s,1H),7.218-7.192(m,2H),6.836-6.818(m,1H),6.759(d,J＝12.5Hz,1H),6.673-6.648(m,1H),4.187(s,1H),4.020-3.989(m,2H),3.466(t,J＝8.0Hz,1H),3.127-3.077(m,1H),2.902(s,3H),2.169-2.054(m,1H),2.036-1.956(m,4H),0.910-0.862(m,1H),0.795-0.770(m,1H),0.555-0.545(m,2H)。
实施例65、73
化合物Z-65以化合物7-a为起始原料，参照实施例63的方法进行制备，不同的是将步骤1中4-溴-2-氯-1-氟苯换成1-溴-4-氯苯。
化合物Z-73以化合物7-a为起始原料，参照实施例63的方法进行制备，不同的是将步骤1中4-溴-2-氯-1-氟苯换成1-溴-4-(三氟甲基)苯，反应条件换成100℃搅拌16小时，步骤2反应条件换成200℃搅拌30分钟，步骤3反应条件换成80℃搅拌16小时。
Figure PCTCN2016073387-appb-000063
实施例64：(R)-5-氯-4-((1-(6-氯吡啶-2-基)吡咯烷-2-基)甲氧基)-2-氟-N-(甲磺酰基)苯甲酰胺(Z-64)的制备
Figure PCTCN2016073387-appb-000064
步骤1：2-氯-6-氟吡啶(2.20g，16.72mmol)，化合物7-a(1.27g，12.54mmol)，碳酸钾(2.31g，16.72mmol)的二甲基甲酰胺(22ml)混合溶液，80℃搅拌5小时。反应结束，冷却至室温，倒入水中，乙酸乙酯萃取，水洗，食盐水洗，干燥分离有机相，减压浓缩。经Combi-flash柱层析纯化得到黄色固体化合物64-b(2g)。MS m/z(ESI):213[M+H]+。
步骤2：以化合物64-b(500mg)为起始原料，参照实施例22步骤2的方法进行制备，不同的是反应条件换成200℃搅拌1小时，得到白色固体化合物Z-64(80mg)，MS m/z(ESI):462[M+H]+。1H NMR(DMSO-d6,400MHz):δ7.78(d,J＝7.6Hz,1H),7.53(d,J＝7.5Hz,1H),7.18(d,J＝12.4Hz,1H),6.64(d,J＝7.2Hz,1H),6.54(d,J＝8.4Hz,1H),4.37-4.26(m,2H),4.06-4.10(m,1H),3.42-3.52(m,2H),2.81(s,3H),2.09-2.05(m,4H).
实施例70
化合物Z-70以化合物7-a为起始原料，参照实施例64的方法进行制备，不同的是将步骤1中2-氯-6-氟吡啶换成2-溴-5-(三氟甲基)吡啶，步骤2中的反应条件换成180℃搅拌30分钟。
Figure PCTCN2016073387-appb-000065
实施例66：(R)-5-氯-4-((1-(5-氯-6-环丙氧基吡啶-3-基)吡咯烷-2-基)甲氧基)-2-氟-N-(甲磺酰基)苯甲酰胺(Z-66)的制备
Figure PCTCN2016073387-appb-000066
步骤1：向化合物20-a(1.5g，7.128mmol)，环丙醇(0.621g，10.692mmol)的N-甲基吡咯烷酮(20ml)的溶液中加入叔丁醇钾(1.2g，10.692mmol)的四氢呋喃(20ml)溶液,室温搅拌1h。反应结束，加入水，分离有机相，食盐水洗，干燥分离有机相，滤液减压浓缩得到粗品，经Combi-flash柱层析纯化得到无色油状化合物66-b(1.58g)，直接用于下一步反应，纯度99.01％，产率89％。MS m/z(ESI):250[M+H]+。
步骤2：以化合物7-a(407mg)为起始原料，参照实施例50步骤1的方法进行制备，不同的是将步骤中将1-溴-4-(三氟甲氧基)苯换成化合物66-b，反应条件换成95℃搅拌过夜，得到白色固体化合物66-c(194mg)，MS m/z(ESI):269.1[M+H]+。
步骤3：以化合物66-c(164mg)为起始原料，参照实施例22步骤2的方法进行制备，不同的是将步骤中反应条件换成200℃搅拌30分钟，得到白色固体化合物Z-66(33.06mg)，MS m/z(ESI):518.1[M+H]+。1H NMR(500MHz,DMSO-d6):δ12.12(br.s.,1H),7.77(d,J＝7.5Hz,1H),7.62(d,J＝2.5Hz,1H),7.40(d,J＝2.5Hz,1H),7.25(d,J＝12.0Hz,1H),4.20-4.17(m,4H),3.49(t,J＝7.5Hz,1H),3.36(s,3H),3.10(q,J＝8.5Hz,1H),2.20(q,J＝10.0Hz,1H),2.10-1.97(m,3H),0.75-0.71(m,2H),0.65-0.62(m,2H).
实施例82：(R)-2-氟-5-甲基-N-(甲磺酰基)-4-((1-(4-(三氟甲基)苯基)吡咯烷-2-基)甲氧基)苯甲酰胺(Z-82)的制备
Figure PCTCN2016073387-appb-000067
步骤1：以化合物7-a(6.08g)为起始原料，参照实施例50步骤1的方法进行制备，不同的是将步骤中1-溴-4-(三氟甲氧基)苯换成1-溴-4-(三氟甲基)苯，反应条件换成100℃搅拌16小时，得到黄色油状化合物82-b(3.98g)，MS m/z(ESI):246.1[M+H]+。
步骤2：以化合物82-b(490mg)为起始原料，参照实施例57步骤3的方法进行制备，不同的是将步骤中化合物17-a换成化合物25-a，反应条件换成室温搅拌2小时，得到无色油状化合物82-c(650mg)，MS m/z(ESI):478.1[M+H]+。
步骤3：以化合物82-c(650mg)为起始原料，参照实施例57步骤4的方法进行制备，不同的是将反应条件换成60℃搅拌2小时，得到白色固体化合物82-d(509mg)，MS m/z(ESI):462.1[M+H]+。
步骤4：以化合物82-d(500mg)为原料，参照化合物11-a中步骤b的制备方法，得到白色固体化合物82-e(150mg)，MS m/z(ESI):539[M+H]+。
步骤5：化合物82-e(50mg，0.093mmol)，甲基硼酸(7mg，0.111mmol)，1,1’-双(二苯膦基)二茂铁二氯化钯(II)(7mg，0.009mmol)，碳酸钠(30mg，0.278mmol)的二氧六环(15ml)混合溶液，100℃搅拌过夜。反应结束，冷却至室温，过滤，滤液减压浓缩，经液相制备纯化得到棕色固体化合物Z-82(7.39mg)。MS m/z(ESI):475.2[M+H]+。1H NMR(500MHz,DMSO-d6):δ7.51(d,J＝8.5Hz,1H),7.46(d,J＝9.0Hz,2H),6.85(d,J＝13.0Hz,1H),6.81(d,J＝8.5Hz,2H),4.33-4.24(br.s.,1H),4.09-4.01(m,2H),3.51(m,1H),3.24-3.20(m,1H),3.13(s,3H),2.22-2.16(m,1H),2.10-1.94(m,6H)
实施例118、120、123-124、143-144、154-155、167-168
化合物Z-118、Z-120、Z-123至Z-124、Z-143至Z-144、Z-154、Z-155、Z-167、 Z-168以化合物7-a为起始原料，参照实施例82的方法进行制备，不同的是根据各自结构，将步骤1中1-溴-4-(三氟甲基)苯或换成2-溴-5-(三氟甲基)吡啶，将步骤4中甲基磺酰胺或分别换成乙烷磺酰胺、环丙烷磺酰胺、异丙烷磺酰胺，将步骤5中甲基硼酸或换成乙基硼酸、异丙基硼酸、环丙基硼酸。
Figure PCTCN2016073387-appb-000068
Figure PCTCN2016073387-appb-000069
Figure PCTCN2016073387-appb-000070
实施例84
化合物Z-84以化合物82-e为起始原料，参照实施例82的方法进行制备，不同的是将步骤5中甲基硼酸换成苯硼酸，反应条件换成100℃氩气保护搅拌4小时。
Figure PCTCN2016073387-appb-000071
实施例83：(R)-2-氟-N-(甲磺酰基)-4-((1-(4-(三氟甲基)苯基)吡咯烷-2-基)甲氧基)苯甲酰胺(Z-83)的制备
Figure PCTCN2016073387-appb-000072
步骤1：以化合物82-b(250mg)为起始原料，参照实施例57步骤3的方法进行制备，不同的是将步骤中化合物17-a换成化合物25-a-1，反应条件换成室温搅拌2小时，得到黄色油状化合物83-c(373mg)，MS m/z(ESI):398.2[M+H]+。
步骤2：以化合物83-c(373mg)为起始原料，参照实施例57步骤4的方法进行制备，得到白色固体化合物83-d(354mg)，MS m/z(ESI):384.2[M+H]+。
步骤3:以化合物83-d(100mg)为起始原料，向50ml单口圆底烧瓶中加入化合物83-d(49mg)，甲磺酰胺(65mg，0.181mmol)，HATU(2-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯)(99mg，0.260mmol)，DIPEA(N，N-二异丙基乙胺)(56mg，0.433mmol)，二甲基甲酰胺3ml，室温搅拌过夜。反应结束，加入20ml水，调节pH为4～5，乙酸乙酯萃取(20ml x 3)，分离有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得到油状物(120mg)，经制备液相分离纯化得白色固体化合物Z-83(3.4mg)，MS m/z(ESI):461.2[M+H]+。
对比例1：(R)-5-氯-4-((1-(4-氯苯甲酰基)吡咯烷-2-基)甲氧基)-2-氟-N-(甲磺酰基)苯甲酰胺(化合物C1)的制备
Figure PCTCN2016073387-appb-000073
步骤1：以化合物(R)-叔丁基-2-(羟甲基)吡咯烷-1-甲酸叔丁酯(1.19g)为原料， 参照实施例22中步骤2的制备方法，将反应条件换成180℃微波搅拌20分钟，得到化合物77-b(375mg)，MS m/z(ESI):351[M+H-100]+。
步骤2：向50ml单口圆底烧瓶中加入化合物77-b(169mg)，盐酸(4M，2ml，8mmol)，3ml甲醇，40℃微波搅拌过夜。反应结束，反应液减压浓缩得到77-c(54mg)，MS m/z(ESI):351[M+H-36]+，直接用于下一步反应，
步骤3：向50ml单口圆底烧瓶中加入4-氯苯甲酸(16mg，0.102mmol)，化合物77-c(40mg，0.102mmol)，2-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯(118mg，0.306mmol)，N，N-二异丙基乙胺(40mg，0.306mmol)，二氯甲烷10ml，室温搅拌1.5h。反应结束，乙酸乙酯和水萃取，分离有机相，减压浓缩，经制备液相分离纯化得化合物C1(5.26mg)，纯度92％，产率10％。MS m/z(ESI):489[M+H]+。1H NMR(500MHz,DMSO):δ7.799(d,J＝6Hz,1H),7.509-7.502m,4H),7.135(d,J＝11.5Hz,1H),4.487-4.453(m,1H),4.318-4.299(m,2H),3.513-3.497(m,1H),2.906(s,3H),2.125-2.022(m,3H),1.796-1.784(m,1H),1.252-1.250(m,1H).
对比例2：(R)-5-氯-2-氟-N-(甲磺酰基)-4-((1-(4-(三氟甲基)苯甲酰基)吡咯烷-2-基)甲氧基)苯甲酰胺(化合物C2)的制备
化合物C2以化合物77-c为起始原料，参照对比例1的方法进行制备，不同的是将步骤3中4-氯苯甲酸换成4-(三氟甲基)苯甲酸。
Figure PCTCN2016073387-appb-000074
对比例3：(R)-5-氯-4-((1-(4-氯苄基)吡咯烷-2-基)甲氧基)-2-氟-N-(甲磺酰基)苯甲酰胺(C3)的制备
Figure PCTCN2016073387-appb-000075
步骤1：向化合物21-a(174mg)的甲醇(10ml)溶液中加入硼氢化钠(25mg，0.622mmol)，室温搅拌2小时。反应结束，加入氯化铵溶液，二氯甲烷萃取，干燥分离有机相，减压浓缩得到白色固体化合物74-b(984mg)。
步骤2：向化合物74-b(182mg)和三乙胺(259mg，2.559mmol)的甲醇(10ml)溶液中0℃加入甲烷磺酰氯(151mg，1.919mmol)，室温搅拌3小时。反应结束，食盐水洗，二氯甲烷萃取，干燥分离有机相，减压浓缩得到黄色油状化合物74-c(265mg)。
步骤3：化合物74-c(124mg，0.563mmol)，化合物22-a(162mg，0.563mmol)，碳酸钾(156mg，1.127mmol)的乙腈(10ml)混合溶液，60℃搅拌2小时。反应结束，冷却至室温，水洗，干燥分离有机相，减压浓缩。经Combi-flash柱层析纯化得到无色油状化合物74-d(147mg)。MS m/z(ESI):412[M+H]+。
步骤4：以化合物74-d(147mg)为起始原料，参照实施例57中步骤4的制备方法，得到白色固体化合物74-e(136mg)，MS m/z(ESI):398.1[M+H]+。
步骤5：以化合物74-e(97mg)为原料，参照化合物11-a中步骤b的制备方法，得到白色固体化合物C3(21.04mg)，MS m/z(ESI):475.1[M+H]+。1H NMR(500MHz,DMSO-d6):δ7.80(d,J＝7.5Hz,1H),7.43(br.s.,4H),7.15(d,J＝12.0Hz,1H),4.47-4.36(m,1H),4.21(s,2H),3.89-3.61(m,1H),3.34(m,2H),3.10(s,3H),2.99-2.93(m,1H),2.14-2.07(m,1H),1.84-1.72(m,3H)
对比例4：(R)-4-((1-(4-(三氟甲基)苄基)吡咯烷-2-基)甲氧基)-5-氯-2-氟-N-(甲磺酰基)苯甲酰胺(C4)的制备
化合物C4以化合物4-(三氟甲基)苯甲醛为起始原料，参照对比例3的方法进行制备。
Figure PCTCN2016073387-appb-000076
阳性对照药物2(Z-0)的制备
Figure PCTCN2016073387-appb-000077
步骤1：将化合物Z-0-1(20.0g,155mmol)溶解在叔丁醇(150mL)中，冷却到0℃，氮气保护下加入叠氮磷酸二苯酯(47g,170mmol),三乙胺(17.3g,170mmol)。混合物回流搅拌18h后，用旋转蒸发仪旋干。残留物溶解在二氯甲烷(400mL)中，用水(200mL x 2)，食盐水(200mL)洗。无水硫酸钠干燥，抽滤。滤液用旋转蒸发仪旋干，残留物用柱层析(PE:EA＝3:1)纯化后得浅黄色固体Z-0-2(15.2g,收率:49％).ESI-MS(M-55)+:145,纯度＝97％(UV214)。1H NMR(400MHz,CDCl3)δ：8.85(brs,1H),8.61(d,1H),7.32(s,1H),1.55(s,9H)。
步骤2：在N2保护下，将Z-0-2(8.0g，0.04mol)溶解在无水THF(80ml)中，混合物冷却到-78℃，滴加LiHMDS(1M，48ml，0.048mol)的THF溶液。滴加完成后，混合物在-78℃，搅拌0.5h。将反应液慢慢升温至室温，搅拌1h，然后降温至-78℃，将5-氯-2,4-二氟苯磺酰氯(11.11g，0.048mol)的THF(50ml)溶液滴加到上述反应液。混合物在-78℃，搅拌1h后升至室温，并在室温搅拌16h。向反应液中加入饱和氯化铵水溶液(250ml)中,用乙酸乙酯(3x 100ml)萃取,合并有机相，用饱和食盐水(200ml)洗，干燥，40℃旋干。粗品过柱(100-200目硅胶),淋洗液为石油醚：乙酸乙酯＝(4:1)，得到Z-0-3(5.11g,产率：31.8％)为白色固体。ESI-MS(M+Na)+:434.0，纯度:95.9％(UV214)。
步骤3：将化合物Z-0-4(50.8g,254mmol)溶解在THF(600mL)中，在冰浴中冷却至0℃搅拌，分批加入氢化锂铝(8.4g,220mmol)。混合物在0℃搅拌2h后，加水淬灭反应，加盐酸(6N)调节PH＝3,分离水相，有机相无水硫酸钠干燥，抽滤。滤液用旋转蒸发仪旋干，得白色固体Z-0-5(32.0g,收率:73.5％).1H NMR(400MHz,CDCl3)δ7.22–7.16(m,1H),6.77(d,J＝8.7Hz,1H),4.61(d,J＝3.7Hz,2H),3.82(s,3H),2.63(s,1H).
步骤4：将化合物Z-0-5(32.0g,190mmol)溶解在二氯甲烷(400mL)中，然后加入氯化亚砜(50mL)。混合物在氮气保护下，加热至回流搅拌3h。混合物降至室温，加水(200mL)淬灭反应，分离有机相，水相用二氯甲烷萃取(200x 2mL)。合并有机相用食盐水洗涤，无水硫酸钠干燥，抽滤。滤液用旋转蒸发仪旋干，得红色固体Z-0-6(33.0g,收率:92.2％)。1H NMR(400MHz,CDCl3)δ7.34(d,J＝2.6Hz,1H),7.25(dd,J＝8.7,2.7Hz,1H),6.81(d,J＝8.8Hz,1H),4.59(s,2H),3.86(s,3H).
步骤5：将化合物Z-0-6(32g,168mmol)溶解在DMSO(200mL)中，加入氰化钠(29g,606mmol)。混合物在氮气保护下，加热至80℃搅拌3h。反应混合物冷却至室温，加水分散，抽滤。滤饼用少量水洗涤。风干得桔红色固体Z-0-7(31g,收率:98.3％)。1H NMR(400MHz,CDCl3)δ7.35(d,J＝2.5Hz,1H),7.28(dd,J＝8.5,2.3Hz,1H),6.82(d,J＝8.7Hz,1H),3.86(s,3H),3.66(s,2H).
步骤6：将化合物Z-0-7(32g,177mmol)溶解在甲酸甲酯(400mL)中，加入钠(8.14g,354mmol)。混合物在氮气保护下，加热回流搅拌24h。反应混合物冷却至室温，加水淬灭反应，乙酸乙酯提取(400x 2mL)，合并有机相水洗(200x 2mL)，无水硫酸钠干燥，抽滤。减压蒸干得黄色固体Z-0-8(10.5g,收率:28.4％)。1H NMR(400MHz,DMSO)δ11.91(s,1H),7.71(d,J＝93.3Hz,1H),7.40–7.32 (m,1H),7.29(dd,J＝12.2,2.6Hz,1H),7.08(dd,J＝8.7,3.1Hz,1H),3.82(s,3H)。
步骤7：将化合物Z-0-8(10.5g,50.2mmol)溶解在乙醇(150mL)中，加入叔丁基肼(7.5g,60.3mmol)。混合物在氮气保护下，加热回流搅拌3.5h。反应混合物冷却至室温，减压蒸干得黄色固体(15g)，快速柱层析得黄色固体Z-0-9(14.0g,收率:99.9％)。
步骤8：将化合物Z-0-9(13.5g,48.4mmol)溶解在二氯甲烷(300mL)中，在冰浴中冷却至0℃，加入三氟乙酸酐(30.5g,145.2mmol)，三乙胺(14.7g,145.2mmol)。混合物在氮气保护下，升至室温搅拌4h。反应混合物加入碳酸钠淬灭反应至中性，分离水相，有机相用饱和食盐水洗涤(100x 2mL)，无水硫酸钠干燥，抽滤。减压蒸干得棕色固体Z-0-10(12.0g,收率:66.1％)。ESI-MS(M-H):376,纯度＝89.23％(UV254).
步骤9：将化合物Z-0-10(11.0g,29.3mmol)溶解在二氯甲烷(200mL)中，在冰浴中冷却至0℃，加入三溴化硼(36.7g,146.6mmol)。混合物在氮气保护下，升至室温搅拌4h。反应混合物慢慢加入冰水(100mL)，分离水相，有机相用饱和食盐水洗涤(100x 2mL)，无水硫酸钠干燥，抽滤。减压蒸干得棕色固体Z-0-11(6.3g,收率:68.9％)。ESI-MS(M-H):362,纯度＝80.83％(UV254).
步骤10：将化合物Z-0-11(25.0g,69mmol)溶解在甲醇(100mL)中，盐酸二氧六环溶液(4M/L,100mL)。混合物在70℃搅拌18h。冷却至室温后，旋干。将氨的甲醇(50mL)溶液慢慢加入到残留物(100mL)，40℃旋干。粗品过柱(100-200目硅胶),淋洗液为二氯甲烷：甲醇(10:1)，得到灰色固体Z-0-12(8.0g,收率:38％)。ESI-MS(M-H):210.1,纯度＝90％(UV214)。
步骤11：将化合物Z-0-12(4.18g,20mmol)，Z-0-3(8.20g,20mmol)，碳酸钾(8.28g,60mmol)溶解在DMF(100mL)中，混合物在氮气保护下，加热至40℃搅拌18h。反应混合物加入水(500mL)，二氯甲烷萃取(200mL x 3)，合并有机相用水洗(100mL x 2)，饱和食盐水洗涤(100x 2mL)，无水硫酸钠干燥，抽滤。减压蒸干得红色固体Z-0-13(15.1g,收率:>100％)。ESI-MS(M+H)+:600.1,纯度＝28％(UV254).
步骤12：将化合物Z-0-13(12.0g,20mmol)溶解在二氯甲烷(40mL)中，加入三氟乙酸(20mL)。混合物在氮气保护下，室温下搅拌24h。减压蒸干得粗产物为黄色固体，经HPLC制备得类白色固体粉末Z-0(3.04mg,收率:31％)。ESI-MS(M+H)+:499.8,纯度＝100％(UV254)。1H NMR(400MHz,DMSO)δ11.56(s,2H),8.91(d,J＝2.4Hz,1H),7.90(d,J＝6.8Hz,1H),7.69(s,1H),7.43(s,1H), 7.32(dd,J＝8.8,2.4Hz,1H),7.22(dd,J＝8.4Hz,1H),7.07(d,J＝2.0Hz,1H),6.73(d,J＝10.8Hz,1H),4.92(s,2H)。
电生理学测定
测试例1hNav1.7和hNav1.5通道的手动膜片钳实验
膜片电压钳电生理学可以直接测量并定量电压门控钠通道(各种Nav)的电流阻断并可以测定阻断的时间和电压依赖，其已被解释为对钠通道的静息、开放和失活状态的结合差异来反映化合物的抑制或激活效应(Hille,B.,Journal of General Physiology(1977),69:497-515)。
本发明代表性的化合物采用手动膜片钳实验进行，本研究的目的是应用手动膜片钳的方法在转染特定离子通道的稳定细胞株上测试化合物对该离子通道电流的作用。其使用的稳定细胞株CHO-hNav1.7和HEK-hNav1.5分别来自Genionics公司和WuXi Apptec(上海)公司。
手动膜片钳实验方案如下：
(一)溶液及化合物的配制：采用全细胞膜片钳技术记录hNav1.7和hNav1.5电流。实验中，细胞外液的组成成分(mM)：HEPES：5,NaCl：40,KCl：3,CaCl2：1,MgCl2：1,CdCl2：0.1,TEA-Cl：20。用NaOH调节pH值至7.3，同时用蔗糖调节渗透压至310-320mOsm，过滤后4℃保存。细胞内液的组成成分(mM)：HEPES：10,NaCl：10,CsOH：5,CsF：140,EGTA：1。用CsOH调节pH值至7.3，同时用蔗糖调节渗透压至280-290mOsm，过滤后-20℃保存。
阳性对照药和待测化合物先溶于100％DMSO(Sigma-Aldrich,D2650，配置成一定浓度(100nM，1000nM)的储备溶液。实验前用DMSO将上述储备溶液进行系列稀释，然后再用细胞外液进一步稀释得到所需浓度的测试溶液。细胞外液中DMSO最终浓度不超过0.30％。
(二)手动膜片钳实验：取细胞悬液加于35mm的培养皿中，置于倒置显微镜载物台上。待细胞贴壁后，用细胞外液灌流，流速为1–2mL/min。玻璃微电极由微电极拉制仪两步拉制，其入水电阻值为2-5MΩ。通过Digidata 1440(Molecular Devices)和pCLAMP软件(10.2版，Molecular Devices)A/D–D/A数模转换，进行刺激发放及信号采集；膜片钳放大器(Multiclamp 700B，Molecular Devices)放大信号，滤波为4KHz。
在hNav1.7和hNav1.5手动膜片钳实验中运用两种不同的电压刺激程序。
一种是失活刺激程序，钳制电位设置在相对应通道的V1/2，即大约50％的通 道处于失活状态。接着给予电压至-120mV，持续50ms。然后去极化至-10mV，持续20ms引出钠电流，最后回到钳制电位。这种刺激程序也可以称之为通道状态依赖的电压刺激程序。
另一种是非失活刺激程序，保持钳制电位在-120mV,给予电压刺激至-10mV，持续20ms引出钠电流，最后回到钳制电位。也就是说在该种刺激程序条件下，所有的通道都没有经历过失活状态，而是直接从静息状态进行激活。
上述两种电压刺激程序的时间间隔均为10s。化合物的抑制效应通过加药前后的电流变化来进行计算，而IC50数值由Hill方程进行拟合所得。如果化合物在上述两种不同的电压刺激下显示出对通道效应有一定倍数的差异，那么该化合物对该通道是具有状态依赖性的。结果分别见表1和表2。
表1本发明代表性化合物在两种浓度下对Nav1.7的抑制率
Figure PCTCN2016073387-appb-000078
Figure PCTCN2016073387-appb-000079
表2本发明代表性化合物在对Nav1.7和Nav1.5的抑制选择性
Figure PCTCN2016073387-appb-000080
表3本发明代表性化合物对Nav1.7和Nav1.5的IC50值
化合物 Nav1.7(IC50/nM) Nav1.5(IC50/nM) Nav1.5/Nav 1.7
Z-22 5.17 600 116
Z-23 24.6 2380 97
Z-41 6.66 4290 644
Z-47 8.23 1500 182
Z-67 5.95 10380 1745
Z-73 5.61 780 139
从表2可以看出，吡咯环碳上的取代位置不同对选择性具有明显的影响。2-位取代的化合物的选择性比3-位取代的化合物的选择性明显提高很多。同时研究发现，当氮原子不与A环(如苯环或吡啶环)直接相连时，即A环(如苯环或吡啶环)通过亚甲基或羰基等基团与氮原子相连时，抑制活性有明显的降低。
从表3可以看出，本发明代表性化合物(如Z-22、Z-23、Z-41、Z-47、Z-67、Z-73)对Nav1.7具有较高的抑制活性，对Nav1.5的抑制活性明显较弱，因此对Nav1.7具有明显的选择抑制活性。
测试例2冷刺激痛觉超敏法SNL
实验动物为雄性Sprague-Dawley大鼠，实验开始时体重140-150g。实验用动物均采购于斯莱克公司，购买后采用自由采食的方式进行食物和水供应，分笼饲养，4只/笼，采用动物尾部标记法进行动物标记。
检测化合物及分组：
溶剂组(Vehicle)：5％二甲基乙酰胺(国药科技)，5％solutol(Sigma)和90％生理盐水
阳性对照物：HYC00012(也称为化合物Z-0)；
待测药物：化合物Z-22，Z-40，Z-47，Z-54，Z-73；
阳性对照物和待测药物的溶剂成分为5％二甲基乙酰胺,5％solutol和90％生 理盐水。
阳性对照物和测试物分别以剂量100mg/kg口服2小时后抑制大鼠脊神经结扎造成的冷痛觉超敏，如表4所示
表4化合物在脊神经结扎大鼠中药效测试分组
Figure PCTCN2016073387-appb-000081
100mg/kg化合物Z-73：称取289.9mg Z-73，加入0.71mL二甲基乙酰胺，待完全溶解后加入0.71mL solutol，震荡混匀后加入90％生理盐水定容至14.24mL，充分混匀后口服给药。
100mg/kg阳性对照物Z-0：称取278.6mg阳性对照物，加入0.68mL二甲基乙酰胺，待完全溶解后加入0.68mL solutol，震荡混匀后加入90％生理盐水定容至13.52mL，完全溶解后口服给药。
实验方法：
1.1.脊神经结扎模型
·手术过程执行无菌操作。
·手术器械(剪刀，镊子，手术刀，手术棉，缝合线，撑开器)在手术前已消毒。
·使用戊巴比妥那(50mg/kg，腹腔注射)麻醉动物。挤压动物脚趾以确认动物手术前已经完全麻醉。在动物眼部涂抹眼用软膏以防止动物角膜干燥。
·剃去动物下半身手术区域毛发，使用碘伏和70％乙醇对手术区域皮肤消毒三遍。待皮肤干燥后开始手术。
·使用手术刀在动物腰部荐骨后部开一纵向切口，暴露左侧椎旁肌，使用撑开器分离肌肉组织以暴露脊椎骨。
·分离左侧脊神经L5和L6，使用6-0丝线结扎。
·缝合伤口。
·清洁手术器械，使用热珠灭菌器灭菌。
·手术后将动物放置在电热毯上，皮下注射5mL生理盐水以防止脱水。等动物完全苏醒后(可自由活动)将动物放回笼中。
1.2.冷痛觉超敏基线测试和分组
给药前两天，对大鼠进行冷痛觉超敏基线测试，使用移液器将100μl丙酮涂在动物术侧后足部皮肤。记录动物在一分钟内拍打，缩脚，抬脚，舔舐术侧足部的时间。丙酮测试共进行两次，两次间隔10分钟。两次时间之和记录为大鼠冷痛觉超敏反应时间。根据给药前一天的冷痛觉超敏反应测试结果将动物随机分组。
1.3.冷痛觉超敏测试
给药两小时后，使用移液器将100μl丙酮涂在动物术侧后脚趾部皮肤。记录动物在一分钟内拍打，缩脚，抬脚，舔舐受影响的脚部的时间。丙酮测试共进行两次，两次间隔10分钟。两次时间之和记录为大鼠冷痛觉超敏反应时间。
1.4.给药
冷刺激痛觉测试2小时前口服给药。
1.5.数据收集和分析
使用Excel软件收集数据。使用Prism软件分析数据。
结论：
表5大鼠冷痛觉超敏测试结果(Z-22)
Figure PCTCN2016073387-appb-000082
表6大鼠冷痛觉超敏测试结果(Z-73)
Figure PCTCN2016073387-appb-000083
表7大鼠冷痛觉超敏测试结果(Z-40)
Figure PCTCN2016073387-appb-000084
表8大鼠冷痛觉超敏测试结果(Z-47，Z-54)
Figure PCTCN2016073387-appb-000085
Figure PCTCN2016073387-appb-000086
实验结果：与图1、3、5和7相比，如图2、图4、图6和图8所示，口服2小时后，本发明示例化合物Z-40、Z-73、Z-22、Z-47和Z-54在脊神经结扎大鼠模型中具有抑制大鼠脊神经结扎诱导的冷痛觉超敏效果，在大鼠体内神经痛模型中是有统计学意义的抑制效果。
图2中，化合物Z-40在脊神经结扎大鼠模型中化合物抑制冷刺激痛觉超敏效果,*p<0.05，***p<0.001。与溶剂组比较，使用单因素方差分析附加Dunnett多重比较检验。口服化合物Z-40和阳性对照物100mg/kg两小时后分别抑制大鼠脊神经结扎诱导的冷痛觉超敏。
图4中，化合物Z-73在脊神经结扎大鼠中的药效，**p<0.01，***p<0.001与溶剂组比较，使用单因素方差分析附加Dunnett多重比较检验。口服化合物Z-73和阳性对照物100mg/kg两小时后分别抑制大鼠脊神经结扎诱导的冷痛觉超敏。
图6中***p<0.001与溶剂组比较，使用单因素方差分析附加Dunnett多重比较检验。口服化合物Z-22和阳性对照物100mg/kg两小时后分别抑制大鼠脊神经结扎诱导的冷痛觉超敏。
图8中，化合物Z-47和Z-54在脊神经结扎大鼠中的药效，*p<0.05，**p<0.01，***p<0.001与溶剂组比较，使用单因素方差分析附加Dunnett多重比较检验。口服Z-47、Z-54和阳性对照物100mg/kg两小时后分别抑制大鼠脊神经结扎诱导的冷痛觉超敏。
测试例4：大鼠体内试验
应用LC/MS/MS法测定了大鼠灌胃给予实施例化合物后不同时刻血浆中的药物浓度，研究本发明化合物在大鼠体内的药代动力学行为，评价其药动学特征。
实验方案：
试验动物：健康成年雄性SD大鼠(体重200-300g，6只，禁食)，由斯莱克公司提供；
给药方式与剂量：给予SD大鼠灌胃给药，给药剂量和口服溶液浓度和配方如下：
表9
Figure PCTCN2016073387-appb-000087
注：C5化合物制法与化合物Z-22类似，其结构式如下：
Figure PCTCN2016073387-appb-000088
血样采集：首先对给药前挑选符合实验要求的动物，称重标记。采集血样前，绑定大鼠，每一只给药的大鼠在预定的采血时间点(灌胃给药：分别于给药前，给药后的0.083,0.25,0.5,1,2,4,8,24h采血,共9个时间点)，通过尾静脉采血，约150μL。血液转移至预先加入K2EDTA的1.5mL试管中。采完的血样放在湿冰上，离心5min(2000g,4℃)，取出血浆，整个过程在采血后15min内完成。所有的样品都需要存放于-70℃冰箱直到样品分析。
应用LC/MS/MS法测定药物浓度，本发明部分实施例化合物在相同给药方式下，大鼠体内的药代动力学性质参数如表10所示：
表10化合物在大鼠体内药代动力学参数
  Z-73 C5
Tmax(hr) 2.0 0.5
半衰期T1/2(hr) 9.73 1.89
口服相对生物利用度F 90.3％ 66.1％
最高血药浓度Cmax(ng/mL) 5695 861
曲线下面积AUC(hr*ng/mL) 67357 1963
从表10可以看出，本发明示例化合物的药代吸收好，具有明显的药代吸收效果，同时表现出更良好的生物利用度(优于C5等对照化合物)。以Z-73为代表的本发明化合物具有更优异的性能，能够以更低地剂量给药，因此安全性更好或毒 副作用更低。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (18)

  1. 一种式(II)所示的化合物，或其药学上可接受的盐、溶剂化物、立体异构体或前药：
    Figure PCTCN2016073387-appb-100001
    式中，
    R1、R2、R3、R4各自独立地为氢、羟基、CN、NO2、卤素、-NRaRb、C1-20烷基、C3-20环烷基、C3-20环烷氧基、C2-20烯基、C2-20炔基、C1-20烷氧基、-CHO、-CO-(C1-20烷基)、-CO-(C6-20芳基)、C6-20芳基、-CONRaRb、-C(O)O-(C1-20烷基)、-OC(O)-(C1-20烷基)、-SO2-(C1-20烷基)或-SO2-(C6-20芳基)；
    R5为氢、C1-20烷基、C3-20环烷基、卤代C1-20烷基；
    R6为C6-20芳基、C1-20烷基、-NRaRb；
    其中，Ra、Rb各自独立地为氢、C1-20烷基、C3-20环烷基或C6-20芳基；
    L1连接在环上的任意不同的位置，为一个键、或-C(O)N(Ry)-、-N(Ry)C(O)-、-N(Ry)SO2-、-SO2N(Ry)-、-OC(O)-、-C(O)O-、-(CRyRx)r1(O)r2(CRyRx)r3-、-S(O)-、-SO2-、-N(Ry)-、-O-、-S-、-C(O)-或亚环丙基；其中，Ry、Rx各自独立地为氢、卤素、羟基、CN、NO2、C1-20烷基、卤代C1-20烷基、C3-20环烷基、C2-20烯基、C2-20炔基或C6-20芳基；r1、r3各自独立地为0、1、2或3；r2为0或1；
    W1、W2各自独立地为C、N、O或S；
    n、m各自独立地为0、1、2或3，且n、m不同时为0；其中，当n为0时或m为0时，W1和W2之间通过单键相连；
    (R0)p为环上的任意位置的氢被p个R0取代，p为0、1、2、3、4或5，每个R0相同或不同，各自独立地为氢、氘、C1-20烷基、氘代C1-20烷基或卤代C1-20烷基；或任意两个R0通过单键或-(CH2)p1-连接，p1为1、2或3；
    A为C6-20芳基、3至7元单环、8至10元双环、3至7元单杂环、8至10元双杂环、5或6元单环杂芳基环、8至10元双环杂芳基环、苯并3至7元单环、苯并3至7元单杂环、5至6元单环杂芳基环并3至7元单环、5至6元单环杂芳基环并3至7元单杂环；
    其中，所述烷基、环烷基、环烷氧基、烯基、炔基、烷氧基、芳基、3至7元单 环、8至10元双环、3至7元单杂环、8至10元双杂环、5或6元单环杂芳基环、8至10元双环杂芳基环、苯并3至7元单环、苯并3至7元单杂环、5至6元单环杂芳基环并3至7元单环、或5至6元单环杂芳基环并3至7元单杂环为取代的或未取代的；且所述的取代是指基团中的1-5个氢被选自下组的取代基所取代：卤素、硝基、羟基、氰基、C6-20芳基、C1-20烷基、卤代C1-20烷基、C1-20烷氧基、卤代C1-20烷氧基、C3-20环烷基、卤代C3-20环烷基、C3-20环烷氧基、卤代C3-20环烷氧基、C2-20烯基、卤代C2-20烯基、C2-20炔基、卤代C2-20炔基、C1-20烷硫基、卤代C1-20烷硫基、C1-20烷基氨基、卤代C1-20烷基氨基、硫醇、3元至20元的杂环烷基、3元至20元的杂环烷基氧基、C3-20环烷硫基、卤代C3-20环烷硫基、3元至20元的杂环烷基硫基、氧代基、C1-20羟烷基、羧基、-NRaRb、-C(O)NRaRb、-N(Ra)C(O)-(C1-20烷基)、-N(Ra)SO2-(C1-20烷基)、-SO2N(RaRb)、-C(O)O-(C1-20烷基)、-CHO、-OC(O)-(C1-20烷基)、-SO2-(C1-20烷基)、-SO2-(C6-20芳基)、-CO-(C6-20芳基)；Ra、Rb各自独立地为氢、C1-20烷基、C3-20环烷基或C6-20芳基；
    并且，
    Figure PCTCN2016073387-appb-100002
    选自：
    Figure PCTCN2016073387-appb-100003
    Figure PCTCN2016073387-appb-100004
    其中，A、L1、R0如上所定义。
  2. 如权利要求1所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药，其特征在于，
    Figure PCTCN2016073387-appb-100005
    选自：
    Figure PCTCN2016073387-appb-100006
    A、L1、R0如权利要求1所定义。
  3. 如权利要求1所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药，其特征在于，A为C6-20芳基或5或6元单环杂芳基环。
  4. 如权利要求1所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药，其特征在于，每个R0相同或不同，各自独立地为氢。
  5. 如权利要求1或3所述的化合物、或其药学上可接受的盐、溶剂化物、立体 异构体或前药，其特征在于，A为苯基或吡啶基；所述的苯基或吡啶基为取代的或未取代的；且所述的取代是指基团中的1-5个氢被选自下组的取代基所取代：卤素、C1-20烷基、卤代C1-20烷基、C1-20烷氧基、卤代C1-20烷氧基、C3-20环烷基、和C3-20环烷氧基。
  6. 如权利要求1所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药，其特征在于，L1为一个键或-(CRyRx)r1(O)r2(CRyRx)r3-；其中，Ry、Rx各自独立地为氢；r1、r3各自独立地为0、1、2或3；r2为0或1。
  7. 如权利要求1或6所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药，其特征在于，L1为-(CRyRx)r1(O)r2(CRyRx)r3-；其中，Ry、Rx各自独立地为氢；r1为1或2；r2为1；r3为0或1。
  8. 如权利要求1所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药，其特征在于，
    Figure PCTCN2016073387-appb-100007
    选自：
    Figure PCTCN2016073387-appb-100008
    L1为一个键或-(CRyRx)r1(O)r2(CRyRx)r3-；其中，Ry、Rx各自独立地为氢；r1、r3各自独立地为0、1、2或3；r2为0或1；
    每个R0相同或不同，各自独立地为氢。
  9. 如权利要求1所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药，其特征在于，所述化合物为式(III)所示化合物：
    Figure PCTCN2016073387-appb-100009
    式中，R0、R1、R2、R3、R4、R5、R6、Rx、Ry、r1、r2、r3、A、W1、W2、n、p、m如权利要求1所定义。
  10. 如权利要求1所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药，其特征在于，所述化合物为式(IV)所示化合物：
    Figure PCTCN2016073387-appb-100010
    式中，R0、R1、R2、R3、R4、R5、R6、Rx、Ry、r1、r2、r3、A、W2、n、p、m如权利要求1定义；W1为N或C。
  11. 如权利要求1所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药，其特征在于，所述化合物为式(V)所示化合物：
    Figure PCTCN2016073387-appb-100011
    式中，R0、R1、R2、R3、R4、R5、R6、L1、W1、W2、n、p、m定义如前；R1’、R2’、R3’、R4’、R5’各自独立地为氢、卤素、硝基、羟基、氰基、C6-20芳基、C1-20烷基、卤代C1-20烷基、卤代C1-20烷氧基、C1-20烷氧基、C3-20环烷基、卤代C3-20环烷基、C3-20环烷氧基、卤代C3-20环烷氧基、C2-20烯基、卤代C2-20烯基、C2-20炔基、卤代C2-20炔基、-NRaRb、-C(O)NRaRb、-N(Ra)C(O)-(C1-20烷基)、-N(Ra)SO2-(C1-20烷基)、-SO2N(RaRb)、-C(O)O-(C1-20烷基)、-CHO、-OC(O)-(C1-20烷基)、-SO2-(C1-20烷基)、-SO2-(C6-20芳基)、-CO-(C1-20烷基)、-CO-(C6-20芳基)；Ra、Rb如权利要求1所定义。
  12. 如权利要求1-11中任一项所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药，其特征在于，R1’、R2’、R3’、R4’、R5’各自独立地为氢、卤素、C1-20烷基、卤代C1-20烷基、卤代C1-20烷氧基、C1-20烷氧基、C3-20环烷基、C3-20环烷氧基。
  13. 如权利要求1-11任一项所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药，其特征在于，
    R1、R2、R3、R4各自独立地为氢、卤素、C1-20烷基、C3-20环烷基；
    R5为氢；和/或
    R6为C1-20烷基、-NRaRb；其中，Ra、Rb各自独立地为氢、或C1-20烷基。
  14. 如权利要求1-10任一项所述的化合物、或其药学上可接受的盐、溶剂化 物、立体异构体或前药，其特征在于，所述苯基为
    Figure PCTCN2016073387-appb-100012
    其中R1’、R2’、R3’、R4’、R5’各自独立地为氢、卤素、C1-20烷基、卤代C1-20烷基、卤代C1-20烷氧基、C1-20烷氧基、C3-20环烷基、C3-20环烷氧基。
  15. 如权利要求1所述的化合物、或其药学上可接受的盐、或其溶剂化物、或其立体异构体、或其前药，其特征在于，所述化合物选自下组：
    Figure PCTCN2016073387-appb-100013
    Figure PCTCN2016073387-appb-100014
    Figure PCTCN2016073387-appb-100015
  16. 如权利要求1所述的化合物、或其药学上可接受的盐、或其溶剂化物、或其立体异构体、或其前药，其特征在于，所述化合物选自下组：
    Figure PCTCN2016073387-appb-100016
  17. 一种药物组合物，所述组合物包括权利要求1至16中任一项所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药；以及药学可接受的载体。
  18. 如权利要求1至16中任一项所述的化合物、或其药学上可接受的盐、溶 剂化物、立体异构体或前药，或如权利要求17所述药物组合物在制备治疗疾病或病症的药物中的应用，所述疾病或病症选自疼痛、抑郁症、心血管疾病、呼吸系统疾病、精神疾病或其组合。
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108430969A (zh) * 2016-02-03 2018-08-21 上海海雁医药科技有限公司 杂环取代的n-磺酰基苯甲酰胺衍生物、其制法与医药上的用途
CN110300745A (zh) * 2017-07-24 2019-10-01 上海海雁医药科技有限公司 钠离子通道抑制剂及其药学上可接受的盐和多晶型物及其应用
WO2020192553A1 (zh) * 2019-03-22 2020-10-01 上海海雁医药科技有限公司 磺酰基取代的苯并杂环甲酰胺衍生物、其制法与医药上的用途

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106905184B (zh) * 2017-03-05 2019-03-29 北京化工大学 含有苯甲酰胺基团的氮芥类化合物及其制备方法和用途
CN109574927A (zh) * 2017-09-29 2019-04-05 浙江海正药业股份有限公司 N-(取代磺酰基)苯甲酰胺类衍生物及其制备方法和医药用途
CN113233957B (zh) * 2021-06-03 2023-05-02 成都工业学院 一种2-溴-5-碘-苄醇的制备方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008128711A1 (en) * 2007-04-23 2008-10-30 Bayer Cropscience Ag Insecticidal aryl pyrrolidines
WO2012007861A1 (en) * 2010-07-12 2012-01-19 Pfizer Limited N-sulfonylbenzamide derivatives useful as voltage gated sodium channel inhibitors
WO2013118805A1 (ja) * 2012-02-08 2013-08-15 大日本住友製薬株式会社 ３位置換プロリン誘導体
WO2013177224A1 (en) * 2012-05-22 2013-11-28 Genentech, Inc. N-substituted benzamides and their use in the treatment of pain
WO2014014050A1 (ja) * 2012-07-19 2014-01-23 大日本住友製薬株式会社 １－（シクロアルキルカルボニル）プロリン誘導体
WO2015078374A1 (en) * 2013-11-27 2015-06-04 Genentech, Inc. Substituted benzamides and methods of use thereof

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2870138B1 (en) * 2012-07-06 2018-08-22 Genentech, Inc. N-substituted benzamides and methods of use thereof
AU2017215697A1 (en) * 2016-02-03 2018-07-05 Shanghai Haiyan Pharmaceutical Technology Co., Ltd. N-sulfonyl benzamide derivative with heterocyclic substituent, preparation method therefor and pharmaceutical application thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008128711A1 (en) * 2007-04-23 2008-10-30 Bayer Cropscience Ag Insecticidal aryl pyrrolidines
WO2012007861A1 (en) * 2010-07-12 2012-01-19 Pfizer Limited N-sulfonylbenzamide derivatives useful as voltage gated sodium channel inhibitors
WO2013118805A1 (ja) * 2012-02-08 2013-08-15 大日本住友製薬株式会社 ３位置換プロリン誘導体
WO2013177224A1 (en) * 2012-05-22 2013-11-28 Genentech, Inc. N-substituted benzamides and their use in the treatment of pain
WO2014014050A1 (ja) * 2012-07-19 2014-01-23 大日本住友製薬株式会社 １－（シクロアルキルカルボニル）プロリン誘導体
WO2015078374A1 (en) * 2013-11-27 2015-06-04 Genentech, Inc. Substituted benzamides and methods of use thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108430969A (zh) * 2016-02-03 2018-08-21 上海海雁医药科技有限公司 杂环取代的n-磺酰基苯甲酰胺衍生物、其制法与医药上的用途
CN110300745A (zh) * 2017-07-24 2019-10-01 上海海雁医药科技有限公司 钠离子通道抑制剂及其药学上可接受的盐和多晶型物及其应用
CN110300745B (zh) * 2017-07-24 2023-03-31 上海海雁医药科技有限公司 钠离子通道抑制剂及其药学上可接受的盐和多晶型物及其应用
WO2020192553A1 (zh) * 2019-03-22 2020-10-01 上海海雁医药科技有限公司 磺酰基取代的苯并杂环甲酰胺衍生物、其制法与医药上的用途

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